Compounds as cannabinoid receptor ligands

ABSTRACT

Disclosed herein are compounds of formula (I) 
                         
wherein R 1 , R 2 , R 3 , R 25a , R 26a , X, and n are as defined in the specification. Pharmaceutical compositions comprising such compounds, and methods of treating conditions and disorders using such compounds and pharmaceutical compositions are also described.

This application is a divisional application of U.S. Patent applicationSer. No. 12/401,788, filed Mar. 11, 2009, which claims the benefit ofU.S. Provisional Application Serial No. 61/035,632, filed Mar. 11, 2008both of which are incorporated herein by reference.

TECHNICAL FIELD

Disclosed herein are compounds that are CB₂ receptor ligands,compositions comprising such compounds, and methods of treatingconditions and disorders using such compounds and pharmaceuticalcompositions thereof.

BACKGROUND

(−)-Δ⁹-Tetrahydrocannabinol (Δ⁹-THC), the major psychoactive constituentof marijuana, exerts a broad range of biological effects through itsinteractions with two cannabinoid (CB) receptor subtypes, CB₁ and CB₂.CB₁ receptors are highly expressed in the central nervous system and toa lesser degree in the periphery in a variety of tissues of thecardiovascular and gastrointestinal systems. By contrast, CB₂ receptorsare most abundantly expressed in multiple lymphoid organs and cells ofthe immune system, including spleen, thymus, tonsils, bone marrow,pancreas and mast cells.

The psychotropic effects caused by Δ⁹-THC and other nonselective CBagonists are mediated by CB₁ receptors. These CB₁ receptor-mediatedeffects, such as euphoria, sedation, hypothermia, catalepsy, andanxiety, have limited the development and clinical utility ofnonselective CB agonists. Recent studies have demonstrated that CB₂modulators are analgesic in preclinical models of nociceptive andneuropathic pain without causing the adverse side effects associatedwith CB₁ receptor activation. Therefore, compounds that selectivelytarget CB₂ receptors are an attractive approach for the development ofnovel analgesics.

Pain is the most common symptom of disease and the most frequentcomplaint with which patients present to physicians. Pain is commonlysegmented by duration (acute vs. chronic), intensity (mild, moderate,and severe), and type (nociceptive vs. neuropathic).

Nociceptive pain is the most well known type of pain, and is caused bytissue injury detected by nociceptors at the site of injury. After theinjury, the site becomes a source of ongoing pain and tenderness. Thispain and tenderness are considered “acute” nociceptive pain. This painand tenderness gradually diminish as healing progresses and disappearwhen healing is complete. Examples of acute nociceptive pain includesurgical procedures (post-op pain) and bone fractures. Even though theremay be no permanent nerve damage, “chronic” nociceptive pain resultsfrom some conditions when pain extends beyond six months. Examples ofchronic nociceptive pain include osteoarthritis, rheumatoid arthritis,and musculoskeletal conditions (e.g., back pain), cancer pain, etc.

Neuropathic pain is defined as “pain initiated or caused by a primarylesion or dysfunction in the nervous system” by the InternationalAssociation for the Study of Pain. Neuropathic pain is not associatedwith nociceptive stimulation, although the passage of nerve impulsesthat is ultimately perceived as pain by the brain is the same in bothnociceptive and neuropathic pain. The term neuropathic pain encompassesa wide range of pain syndromes of diverse etiologies. The three mostcommonly diagnosed pain types of neuropathic nature are diabeticneuropathy, cancer neuropathy, and HIV pain. In addition, neuropathicpain is diagnosed in patients with a wide range of other disorders,including trigeminal neuralgia, post-herpetic neuralgia, traumaticneuralgia, phantom limb, as well as a number of other disorders ofill-defined or unknown origin.

Managing the spectrum of pain etiologies remains a major public healthproblem and both patients and clinicians are seeking improved strategiesto effectively manage pain. No currently available therapies or drugseffectively treat all types of nociceptive and neuropathic pain states.Compounds described herein are novel CB₂ receptor modulators that haveutility in treating pain, including nociceptive and neuropathic pain.

SUMMARY

Provided generally herein are compounds that are CB₂ receptor ligandsand pharmaceutical compositions and methods for the treatment ofdisorders using these compounds and pharmaceutical compositions.

Presented herein are compounds of formula (I)

and pharmaceutically acceptable salts, solvates, prodrugs, salts ofprodrugs, or any combinations thereof, wherein

X is CR⁴ or N;

R¹ is phenyl or quinolin-8-yl wherein said phenyl is substituted withone group represented by R¹⁰ and optionally further substituted with 1,2, or 3 groups represented by R^(11a); and wherein said quinolin-8-yl isoptionally substituted with 1 or 2 groups represented by R^(11b);

R² is —NR^(23a)SO₂R^(105a), —NR^(23b)COR^(105b), —NR^(23b)CO(O)R^(105b),—NR²³CONR^(101a)R^(102a), —NR^(23d)SO₂NR^(101b)R^(102b), —NR^(23e)R²⁴,—SO₂NR^(101e)R^(102e), —OC(O)NR^(101a)R^(102a), A¹, A², or A³; with theproviso that when X is CR⁴, R¹ is substituted phenyl, and R² is—OC(O)NR^(101a)R^(102a) wherein R^(101a) and R^(102a) are eachindependently hydrogen, alkyl, alkoxyalkyl, cycloalkyl, haloalkyl, orhaloalkoxyalkyl, then R¹⁰ is other than haloalkoxyalkoxy,—O—NR^(23f)R^(23g), —O—(CR^(25b)R^(26b))_(u)-A⁴,—O—(CR^(25b)R^(26b))_(u)—C(═S)NR^(101d)R^(102d),—O—(CR^(25b)R^(26b))_(u)—C(O)NR^(101d)R^(102d),—O—(CR^(25b)R^(26b))_(u)—SO₂NR^(101d)R^(102d), and—O—(CR^(25b)R^(26b))_(q)—NR¹⁰³R¹⁰⁴;

A¹ is a monocyclic heterocycle containing 1 or 2 nitrogen atoms and 0 or1 sulfur atoms, wherein each A¹ is independently unsubstituted orsubstituted with 1, 2, or 3 substituents represented by R^(21a);

A² is a bicyclic spiroheterocycle containing 1 or 2 nitrogen atoms and 0or 1 sulfur atoms, wherein each A² is independently unsubstituted orsubstituted with 1, 2, or 3 substituents represented by R^(21b);

A³ is imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl,isothiazolyl, triazolyl, or pyridinyl, wherein each A³ is independentlyunsubstituted or substituted with 1, 2, or 3 substituents represented byR^(22a);

-   -   R³ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,        cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, halo,        cyano, or cyanoalkyl; with the proviso that when n is 1, R¹ is        substituted phenyl, X is CR⁴ wherein R⁴ is hydrogen, R² is A³,        and A³ is pyridinyl or 1,3-thiazolyl, then R³ is other than        hydrogen;

R⁴ is alkyl, alkenyl, alkynyl, cycloalkyl, hydrogen, or haloalkyl;

R¹⁰ is alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkenyl, alkynyl,alkylcarbonyl, cycloalkylalkyl, cyano, cyanoalkyl, formyl, halo,haloalkoxy, haloalkoxyalkoxy, haloalkyl, —CR^(106a)(═N—OR^(106b)),—O—NR^(23f)R^(23g), —O—(CR^(25b)R^(26b))_(u)-A⁴,—O—(CR^(25b)R^(26b))_(u)—C(═O)NR^(101d)R^(102d),—O—(CR^(25b)R^(26b))_(u)—C(═S)NR^(101d)R^(102d),—O—(CR^(25b)R^(26b))_(u)—SO₂NR^(101d)R^(102d),—O—(CR^(25b)R^(26b))_(q)—NR¹⁰³R¹⁰⁴, —NR^(23f)R^(23g),—NR^(23f)—(CR^(25b)R^(26b))_(u)-A⁴,—NR^(23f)—(CR^(25b)R^(26b))_(u)—C(═O)NR^(101d)R^(102d),—NR^(23f)—(CR^(25b)R^(26b))_(u)—C(═S)NR^(101d)R^(102d),—NR^(23f)—(CR^(25b)R^(26b))_(u)—SO₂NR^(101d)R^(102d),—NR^(23f)—(CR^(25b)R^(26b))_(q)—NR¹⁰³R¹⁰⁴, or A⁴;

R^(11a) and R^(11b), at each occurrence, are each independently alkoxy,alkyl, alkenyl, alkynyl, alkylcarbonyl, cycloalkyl, cycloalkyloxy,cyano, cyanoalkyl, formyl, halo, haloalkoxy, haloalkoxyalkoxy,haloalkyl, —CR^(106a)(═N—OR^(106b)), furanyl, oxazolyl, oxadiazolyl,isoxazolyl, triazolyl, pyrazolyl, thiazolyl, oxetanyl,tetrahydrofuranyl, or pyranyl;

R^(21a), R^(21b), R^(21c), and R^(21d), at each occurrence, are eachindependently alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkoxy,alkoxyalkyl, halo, haloalkyl, haloalkoxy, haloalkoxyalkyl, oxo, ═S,hydroxy, cyano, cyanoalkyl, ═N—CN, ═N—OR^(106b),—CR^(106a)(═N—OR^(106b)), —CONR^(101d)R^(102d), —SO₂NR^(101d)R^(102d),—COR^(105d), —C(O)OR^(105c), or —SO₂R^(105c);

R^(22a) and R^(22b), at each occurrence, are each independently alkyl,alkenyl, alkynyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, halo, haloalkyl,haloalkoxy, haloalkoxyalkyl, hydroxy, cyano, cyanoalkyl,—CR^(106a)(═N—OR^(106b)), —CONR^(101d)R^(102d), —SO₂NR^(101d)R^(102d),—COR^(105d), —C(O)OR^(105c), or —SO₂R^(105c);

R^(23a), R^(23b), R^(23c), R^(23d), R^(23e), R^(23f), and R^(23g) areeach independently hydrogen, alkyl, cycloalkyl, haloalkyl, alkoxyalkyl,or haloalkoxyalkyl;

R²⁴ is alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, or A⁵;

A⁴ and A⁵, at each occurrence, are each independently a cycloalkyl, amonocyclic heterocycle that is optionally substituted with 1, 2, or 3substituents represented by R^(21c); a bicyclic spiroheterocycle that isoptionally substituted with 1, 2, or 3 substituents represented byR^(21d); or a monocyclic heteroaryl that is optionally substituted with1, 2, or 3 substituents represented by R^(22b);

R^(25a) and R^(26a), at each occurrence, are each independentlyhydrogen, alkyl, cyclopropyl, cyclobutyl, cyclopentyl, halo, haloalkyl,or alkoxy; R^(25a) and R^(26a) taken together with the carbon atom towhich they are attached optionally form a monocyclic ring selected fromthe group consisting of cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl; wherein each of the cyclopropyl, cyclobutyl, cyclopentyl,and cyclohexyl is independently unsubstituted or substituted with 1, 2,3, 4, 5, or 6 substituents independently selected from the groupconsisting of alkyl, halo, haloalkyl, alkoxy, oxo, hydroxy, cyano, andhaloalkoxy;

R^(25b) and R^(26b), at each occurrence, are each independentlyhydrogen, alkyl, cyclopropyl, cyclobutyl, cyclopentyl, halo, haloalkyl,or alkoxy;

R^(101a), R^(101b), R^(101c), R^(102a), R^(102b), and R^(102c), at eachoccurrence, are each independently hydrogen, alkyl, alkoxyalkyl,cycloalkyl, haloalkyl or haloalkoxyalkyl; R^(101a) and R^(102a), orR^(101b) and R^(102b), or R^(101c) and R^(102c), together with therespective nitrogen atom to which they are attached optionally form a4-7 membered monocyclic heterocycle; wherein said monocyclic heterocyclecontains 0 or 1 additional heteroatom, 0 or 1 double bond, and isoptionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of alkyl, alkoxy, haloalkyl, halo,hydroxy, and oxo;

R^(101d) and R^(102d), at each occurrence, are each independentlyhydrogen, alkyl, alkoxyalkyl, cycloalkyl, haloalkyl or haloalkoxyalkyl;R^(101d) and R^(102d), together with the nitrogen atom to which they areattached, optionally form a 4-7 membered monocyclic heterocycle; whereinsaid monocyclic heterocycle contains 0 or 1 additional heteroatom, 0 or1 double bond, and is optionally substituted with 1, 2, or 3substituents independently selected from the group consisting of alkyl,alkoxy, haloalkyl, halo, hydroxy, and oxo;

R¹⁰³ is hydrogen, alkyl, haloalkyl, or alkoxyalkyl;

R¹⁰⁴ is hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, alkoxyalkyl,cycloalkyl, haloalkyl, or haloalkoxyalkyl;

R^(105a), R^(105b), and R^(105c), at each occurrence, are eachindependently alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl,haloalkyl, or cyanoalkyl;

R^(105d), at each occurrence, is independently hydrogen, alkyl,cycloalkyl, cycloalkylalkyl, alkoxyalkyl, haloalkyl, or cyanoalkyl;

R^(106a) and R^(106b), at each occurrence, are each independentlyhydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl,isobutyl, tert-butyl, cyclopropyl, or cyclobutyl;

n is 1, 2, 3, or 4;

u is 0, 1, 2, 3, or 4;

q is 2, 3, or 4, and

each occurrence of the cycloalkyl, the cycloalkyl moiety of thecycloalkylalkyl and the cycloalkyloxy, the cyclopropyl, the cyclobutyl,and the cyclopentyl, as represented by R³, R⁴, R¹⁰, R^(11a), R^(11b),R^(23a), R^(23b), R^(23c), R^(23d), R^(23e), R^(23f), R^(23g), A⁴, A⁵,R^(25a), R^(26a), R^(25b), R^(26b), R^(101a), R^(101b), R^(101c),R^(101d), R^(102a), R^(102b), R^(102c), R^(102d), R¹⁰⁴, R^(105a),R^(105b), R^(105c), R^(105d), R^(106a), and R^(106b), are eachindependently unsubstituted or substituted with 1, 2, 3, 4, 5, or 6substituents independently selected from the group consisting of alkyl,halo, haloalkyl, alkoxy, oxo, hydroxy, cyano, and haloalkoxy.

Another aspect relates to pharmaceutical compositions comprisingtherapeutically effective amount of compound(s) described herein orpharmaceutically acceptable salts thereof, in combination with one ormore pharmaceutically acceptable carriers. Such compositions can beadministered in accordance with methods described herein, typically aspart of a therapeutic regimen for treatment or prevention of conditionsand disorders related to cannabinoid (CB) receptor subtype CB₂. Moreparticularly, the method is useful for treating conditions related toneuropathic pain, nociceptive pain, inflammatory pain, neurologicaldisorders, cancers of the immune system, respiratory disorders, obesity,diabetes, cardiovascular disorders, or for providing neuroprotection.

Yet another aspect relates to methods for treating disease or conditionsas described above, or providing neuroprotection, in mammals in need ofsuch treatment. These methods comprise administering to the mammalstherapeutically effective amounts of one or more compounds describedherein, or pharmaceutically acceptable salts, prodrugs, solvatesthereof, or combinations thereof, alone or in combination with one ormore pharmaceutically acceptable carriers.

A further aspect relates to the use of compounds described herein orpharmaceutically acceptable salt(s) thereof, in the manufacture of amedicament for the treatment of the disease conditions described above,alone or in combination with one or more pharmaceutically acceptablecarrier(s), particularly for the treatment of neuropathic pain,nociceptive pain, inflammatory pain, or combination thereof.

The compounds, compositions comprising the compounds, and methods fortreating or preventing conditions and disorders by administering thecompounds are further described herein.

These and other objectives are described in the following paragraphs.These objectives should not be deemed to narrow the scope of theinvention.

DETAILED DESCRIPTION

Compounds of formula (I) are disclosed

wherein R¹, R², R³, R^(25a), R^(26a), X, and n are as defined above inthe Summary and below in the Detailed Description. Compositionscomprising such compounds and methods for treating conditions anddisorders using such compounds and compositions are also disclosed.

In various embodiments, compounds described herein may contain variablesthat occur more than one time in any substituent or in the compounddescribed or any other formulae herein. Definition of a variable on eachoccurrence is independent of its definition at another occurrence.Further, combinations of substituents are permissible only if suchcombinations result in stable compounds. Stable compounds are compounds,which can be isolated from a reaction mixture.

a. Definitions

As used in the specification and the appended claims, unless specifiedto the contrary, the following terms have the meaning indicated:

The term “alkenyl” as used herein, means a straight or branchedhydrocarbon chain containing from, for example, 2 to 10 carbons andcontaining at least one carbon-carbon double bond. Representativeexamples of alkenyl include, but are not limited to, ethenyl,2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl,2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term “alkenylene” denotes a divalent group derived from a straightor branched hydrocarbon chain of, for example, 2, 3, or 4 carbon atomsand contains at least one carbon-carbon double. Representative examplesof alkenylene include, but are not limited to, —CH═CH— and —CH₂CH═CH—.

The term “alkoxy” as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, andhexyloxy.

The term “alkoxyalkoxy” as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through anotheralkoxy group, as defined herein. Representative examples of alkoxyalkoxyinclude, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy,2-methoxyethoxy, and methoxymethoxy.

The term “alkoxyalkyl” as used herein, means an alkoxy group, as definedherein, appended to the parent molecular moiety through an alkylenegroup, as defined herein. Representative examples of alkoxyalkylinclude, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl,2-methoxyethyl, and methoxymethyl.

The term “alkyl” as used herein, means a saturated, straight or branchedsaturated hydrocarbon chain containing from, for example, 1 to 10 carbonatoms. The term “C₁₋₆ alkyl” as used herein, means a saturated, straightor branched saturated hydrocarbon chain containing from 1 to 6 carbonatoms. Representative examples of alkyl include, but are not limited to,methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl,tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 1-methylbutyl,2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl,2,2-dimethylpropyl, 1-methylpropyl, 1-ethylpropyl,1,2,2-trimethylpropyl, 3-methylhexyl, 2,2-dimethylpentyl,2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

The term “alkylcarbonyl” as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through a C(═O)group.

The term “alkylene” means a divalent group derived from a saturated,straight or branched saturated hydrocarbon chain of from, for example, 1to 10 carbon atoms. Representative examples of alkylene include, but arenot limited to, —CH₂—, —CH(CH₃)—, —CH(C₂H₅), —CH(CH(CH₃)(C₂H₅))—,—C(H)(CH₃)CH₂CH₂—, —C(CH₃)₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and—CH₂CH(CH₃)CH₂—.

The term “alkynyl” as used herein, means a straight or branchedhydrocarbon chain containing from, for example, 2 to 10 carbon atoms andcontaining at least one carbon-carbon triple bond. Representativeexamples of alkynyl include, but are not limited, to acetylenyl,1-propynyl, 2-propynyl, 1,1-dimethylprop-2-ynyl, 1-propyl-pent-3-ynyl,3-butynyl, 2-pentynyl, and 1-butynyl.

The term “bicyclic spiroheterocycle” or “bicyclic spiroheterocyclic” asused herein refers to a monocyclic heterocycle having two or moresubstituents wherein two substituents on the same carbon atom, togetherwith said carbon atom, form a second 4-, 5-, or 6-membered monocyclicring selected from a monocyclic cycloalkyl or a monocyclic heterocycle.The bicyclic spiroheterocyclic groups are connected to the parentmolecular moiety through any substitutable carbon atom or anysubstitutable nitrogen atom contained within the group. The bicyclicspiroheterocyclic groups described herein may also contain an alkenylenebridge of 2, 3, or 4 carbon atoms, or an alkylene bridge of 1, 2, 3, or4 carbon atoms, wherein each bridge links two non-adjacent carbon atomswithin the groups. Examples of bicyclic spiroheterocycles include, butare not limited to, 2-azaspiro[bicyclo[2.2.1]heptane-6,1′-cyclopropane],2-oxa-5-azaspiro[3.4]octane, 5-azaspiro[2.4]heptane,5-oxaspiro[3,4]octane and 2,5-dioxaspiro[3.4]octane.

The term “cycloalkyl” as used herein, means a carbocyclic ring systemcontaining 3, 4, 5, 6, 7, or 8 carbon atoms and zero heteroatoms as ringatoms, and zero double bonds. Examples of cycloalkyls include, but arenot limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. The cycloalkyl groups described herein maycontain one or two alkylene bridges of 1, 2, 3, or 4 carbon atoms or oneor two alkenylene bridges of 2, 3, or 4 carbon atoms, wherein each ofsaid bridges links two non-adjacent atoms within the cycloalkyl.Examples of such bridged cycloalkyls include, but are not limited to,adamantane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane,bicyclo[2.2.2]octane, bicyclo[3.3.1]nonane. The cycloalkyl groups of thedescribed herein can be appended to the parent molecular moiety throughany substitutable carbon atom.

The term “cycloalkylalkyl” as used herein, means a cycloalkyl group, asdefined herein, appended to the parent molecular moiety through analkylene group, as defined herein. Representative examples ofcycloalkylalkyl include, but are not limited to, cyclopentylmethyl,cyclohexylmethyl, cyclopropylmethyl, and 1-cyclopropylethyl.

The term “cycloalkyloxy,” as used herein means a cycloalkyl group, asdefined herein, appended to the parent molecular moiety through anoxygen atom.

The term “cyano,” as used herein, means a —CN group.

The term “cyanoalkyl,” as used herein, means a cyano group, as definedherein, appended to the parent molecular moiety through an alkylenegroup, as defined herein. Representative examples of cyanoalkyl include,but are not limited to, cyanomethyl, 2-cyanoethyl, and 3-cyanopropyl.

The term “formyl,” as used herein, means a —C(O)H group.

The term “halo” or “halogen,” as used herein, means —Cl, —Br, —I or —F.

The term “haloalkoxy,” as used herein, means an alkoxy group, as definedherein, in which one, two, three, four, five, or six hydrogen atoms arereplaced by halogen. Representative examples of haloalkoxy include, butare not limited to, trifluoromethoxy, difluoromethoxy,2,2,2-trifluoroethoxy, 2,2-difluoroethoxy, 2-fluoroethoxy, andpentafluoroethoxy.

The term “haloalkoxyalkoxy,” as used herein, means a haloalkoxy group,as defined herein, appended to the parent molecular moiety through analkoxy group, as defined herein.

The term “haloalkoxyalkyl,” as used herein, means a haloalkoxy group, asdefined herein, appended to the parent molecular moiety through analkylene group, as defined herein.

The term “haloalkyl,” as used herein, means an alkyl group, as definedherein, in which one, two, three, four, five, six, or seven hydrogenatoms are replaced by halogen. Representative examples of haloalkylinclude, but are not limited to, chloromethyl, 2-fluoroethyl,2,2-difluoroethyl, trifluoromethyl, 2,2,2-trifluoroethyl,2,2,2-trifluoro-1,1-dimethylethyl, difluoromethyl,3,3,3-trifluoropropyl, pentafluoroethyl, 2-chloro-3-fluoropentyl, and2-iodoethyl.

The term “monocyclic heteroaryl,” as used herein, means a 5- or6-membered ring containing at least one heteroatom independentlyselected from the group consisting of O, N, and S. The 5-membered ringcontains two double bonds and one, two, three, or four heteroatoms. The6-membered ring contains three double bonds and one, two, three, or fourheteroatoms. Non limiting examples of monocyclic heteroaryl include,furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl,pyridinyl (including but not limited to, pyridin-2-yl, pyridin-3-yl),pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl (e.g. pyrazol-5-yl),pyrrolyl (including, but not limited thereto, 1H-pyrrol-1-yl),tetrazolyl, thiadiazolyl, thiazolyl (including, but not limited thereto,1,3-thiazol-4-yl, 1,3-thiazol-2-yl, and 1,3-thiazol-5-yl), thienyl,triazolyl, triazinyl, and the like. The monocyclic heteroaryl groups areconnected to the parent molecular moiety through any substitutablecarbon atom or any substitutable nitrogen atom contained within thegroups. Any oxidized forms of nitrogen or sulfur in the monocyclicheteroaryl groups are also contemplated.

The term “heteroatom” includes an oxygen atom, a nitrogen atom, and asulfur atom.

The term “monocyclic heterocycle” or “monocyclic heterocyclic,” as usedherein, means a a 3-, 4-5-, 6-, 7-, or 8-membered monocyclic ringcontaining at least one heteroatom independently selected from the groupconsisting of O, N, and S. The 3- or 4-membered ring contains 1heteroatom selected from the group consisting of O, N and S, andoptionally one double bond. The 5-membered ring contains zero or onedouble bond, and one, two or three heteroatoms in the ring selected fromthe group consisting of O, N and S. The 6-, 7-, or 8-membered ringcontains zero, one, or two double bonds, and one, two, or threeheteroatoms in the ring selected from the group consisting of O, N andS. Non limiting examples of monocyclic heterocycles include, azetidinyl(including azetidin-1-yl, azetidin-2-yl, azetidin-3-yl), azepanyl,aziridinyl, diazepanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl,4,5-dihydroisoxazol-5-yl, 3,4-dihydropyran-6-yl, 1,3-dithiolanyl,1,3-dithianyl, imidazolinyl, imidazolidinyl (e.g. imidazolidin-1-yl),isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl,morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl,oxetanyl, piperazinyl, piperidinyl (e.g. piperidin-1-yl, piperidin-2-yl,piperidin-3-yl), pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl,pyrrolidinyl (including, but not limited thereto, pyrrolidin-1-yl,pyrrolidin-2-yl), tetrahydrofuranyl (including tetrahydrofuran-2-yl andtetrahydrofuran-3-yl), tetrahydropyranyl, tetrahydrothienyl,thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl,thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone),thiopyranyl, trithianyl, and the like. Monocyclic heterocycle groupsdescribed herein may contain an alkenylene bridge of 2, 3, or 4 carbonatoms, or one or two alkylene bridges of 1, 2, 3, or 4 carbon atoms,wherein each bridge links two non-adjacent carbon atoms within thegroups. Examples of such bridged heterocycles include, but are notlimited to, 2-oxa-5-azabicyclo[2.2.1]heptane,2-azabicyclo[2.2.1]heptane, oxaadamantane(2-oxatricyclo[3.3.1.1^(3,7)]decane), octahydro-2,5-epoxypentalene,hexahydro-2H-2,5-methanocyclopenta[b]furan,hexahydro-1H-1,4-methanocyclopenta[c]furan, oxabicyclo[2.2.1]heptane and2,4-dioxabicyclo[4.2.1]nonane. The monocyclic heterocycle groups areconnected to the parent molecular moiety through any substitutablecarbon atom or any substitutable nitrogen atom contained within thegroups. Any oxidized form of nitrogen or sulfur, and the quarternizedform of any basic nitrogen in the monocyclic heterocycle groups are alsocontemplated.

The term “hydroxy” as used herein, means an —OH group.

The term “hydroxyalkyl” as used herein, means at least one hydroxygroup, as defined herein, is appended to the parent molecular moietythrough an alkylene group, as defined herein. Representative examples ofhydroxyalkyl include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxyprop-2-yl,2,3-dihydroxypentyl, and 2-ethyl-4-hydroxyheptyl.

The term “hydroxy-protecting group” or “O-protecting group” means asubstituent that protects hydroxy groups against undesirable reactionsduring synthetic procedures. Examples of hydroxy-protecting groupsinclude, but are not limited to, substituted methyl ethers, for example,methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl,2-(trimethylsilyl)-ethoxymethyl, benzyl, and triphenylmethyl;tetrahydropyranyl ethers; substituted ethyl ethers, for example,2,2,2-trichloroethyl and t-butyl; silyl ethers, for example,trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl; cyclicacetals and ketals, for example, methylene acetal, acetonide andbenzylidene acetal; cyclic ortho esters, for example, methoxymethylene;cyclic carbonates; and cyclic boronates. Commonly usedhydroxy-protecting groups are disclosed in T. W. Greene and P. G. M.Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley &Sons, New York (1999).

The term “oxo” means ═O.

The term “treating” means, and includes, reversing, alleviating,inhibiting the progress of, or preventing, a disease, a disorder, orcondition, or one or more symptoms thereof; and, “treatment” refer tothe act of treating, as defined above.

The term “mammal” means humans and other animals.

b. Compounds

Compounds of formula (I) are as described above.

Particular values of variable groups in compounds of formula (I) are asfollows. Such values may be used where appropriate with any of the othervalues, definitions, claims or embodiments defined hereinbefore orhereinafter.

As described generally above for compounds of formula (I), R¹ issubstituted phenyl or optionally substituted quinolin-8-yl.

In certain embodiments, R¹ is phenyl, substituted as described in theSummary, for example, R¹ is formula (i)

wherein y is 0, 1, 2, or 3, and R¹⁰ and R^(11a) are as describedgenerally in the Summary and embodiments hereinafter.

Thus, included herein are compounds of formula (I-A)

wherein y is 0, 1, 2, or 3, R², R³, n, X, R¹⁰, R^(11a), R^(25a), andR^(26a) are each described generally in the Summary and in embodimentsdescribed herein.

In conjunction with any of the above or below embodiments, y is 0 or 1.

Certain compounds described herein include those wherein R¹ is formula(I) wherein y is 1, for example, such as those represented by formula(ii)

Compounds of formula (I) wherein R¹ is formula (II) are represented byformula (I-B)

wherein R², R³, n, X, R¹⁰, R^(11a), R^(25a), and R^(26a) are eachdescribed generally in the Summary and in embodiments described herein.

In yet other embodiments, R¹ is formula (iii)

Compounds containing R¹ having formula (iii) are represented by formula(I-C)

wherein R², R³, n, X, R¹⁰, R^(11a), R^(25a), and R^(26a) are eachdescribed generally in the Summary and in embodiments described herein.

In yet certain embodiments, R¹ is quinolin-8-yl, optionally substitutedwith 1 or 2 R^(11b) groups, such as those represented by formula (iv)

wherein z is 0, 1, or 2, and R^(11b), at each occurrence, represents anoptional substituent on any one of the substitutable carbon atoms of thequinoline ring.

Thus, included in the present application are compounds of formula (I)wherein R¹ is formula (iv), as represented by formula (I-D)

wherein z is 0, 1, or 2, R², R³, n, X, R^(11b), R^(25a), and R^(26a) areeach described generally in the Summary and in embodiments describedherein.

In yet certain embodiments, R¹ is formula (v)

Thus, included in the present application are compounds of formula (I-E)

wherein R², R³, n, X, R^(11b), R^(25a), and R^(26a) are each describedgenerally the Summary and in embodiments described herein.

R¹⁰ has values as generally described in the Summary. In certainembodiments, R¹⁰ is, for example, haloalkoxyalkoxy, —O—NR^(23f)R^(23g),O—(CR^(25b)R^(26b))_(u)-A⁴,—O—(CR^(25b)R^(26b))_(u)—C(═O)NR^(101d)R^(102d),—O—(CR^(25b)R^(26b))_(u)—C(═S)NR^(101d)R^(102d),—O—(CR^(25b)R^(26b))_(u)—SO₂NR^(101d)R^(102d), or—O—(CR^(25b)R^(26b))_(q)—NR¹⁰³R¹⁰⁴. In other embodiments, R¹⁰, forexample, is alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkenyl, alkynyl,alkylcarbonyl, cycloalkylalkyl, cyano, cyanoalkyl, formyl, halo,haloalkoxy, haloalkyl, —CR^(106a)(═N—OR^(106b)), —NR^(23f)R^(23g),—NR^(23f)—(CR^(25b)R^(26b))_(u)-A⁴,—NR^(23f)—(CR^(25b)R^(26b))_(u)—C(═O)NR^(101d)R^(102d),—NR^(23f)—(CR^(25b)R^(26b))_(u)—C(═S)NR^(101d)R^(102d),—NR^(23f)—(CR^(25b)R^(26b))_(u)—SO₂NR^(101d)R^(102d),—NR^(23f)—(CR^(25b)R^(26b))_(q)—NR¹⁰³R¹⁰⁴, or A⁴. In yet otherembodiments, R¹⁰, for example, is alkoxy (e.g. methoxy, ethoxy, and thelike), haloalkoxy, haloalkyl, halo (e.g., chloro, fluoro, and the like),—O—NR^(23f)R^(23g), —O—(CR^(25b)R^(26b))_(u)-A⁴, or A⁴. R^(23f),R^(23g), R^(25b), R^(26b), R^(101d), R^(102d), R¹⁰³, R¹⁰⁴, R^(106a),R^(106b), q, u, and A⁴ are as described in the Summary and theembodiments herein below. For example, R^(25b) and R^(26b) are eachindependently hydrogen or C₁₋₆ alkyl (e.g., methyl). R^(23f), forexample, is hydrogen. R^(23g), for example, is alkyl (e.g. tert-butyl).A⁴, for example, is a monocyclic heterocyle (e.g. azetidinyl such as,azetidin-1-yl, azetidin-2-yl, azetidin-3-yl), optionally substitutedwith 1, 2, or 3 substituents represented by R^(21c), or a monocyclicheteroaryl (e.g. pyridinyl such as pyridin-2-yl and the like),optionally substituted with 1, 2, or 3 substituents represented byR^(21d) wherein R^(21c) and R^(21d) are as described in the Summary. u,for example, is 0 or 1.

In other embodiments, R¹⁰, for example, is

—O—NR^(23f)R^(23g) wherein R^(23f) is hydrogen and R^(23g), for example,is alkyl (e.g. tert-butyl);

—O—(CR^(25b)R^(26b))_(u)-A⁴ wherein R^(25b) and R^(26b) are eachindependently hydrogen or C₁₋₆ alkyl (e.g., methyl), u is 0 or 1, andA⁴, for example, is a monocyclic heterocyle (e.g. azetidinyl such as,azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, pyrrolidin-2-yl,pyrrolidin-3-yl), optionally substituted with 1, 2, or 3 substituentsrepresented by R^(21c), or a monocyclic heteroaryl (e.g. pyridinyl suchas pyridin-2-yl and the like), optionally substituted with 1, 2, or 3substituents represented by R^(21d);

alkoxy (e.g. methoxy, ethoxy);

haloalkoxy (trifluoroethoxy);

halo (e.g. chloro, bromo, fluoro); or

optionally substituted monocyclic heterocycle (e.g. optionallysubstituted azetidinyl).

R^(11a) and R^(11b) have values as generally described in the Summary.In certain embodiments, R^(11a) and R^(11b) are each independentlycyano, haloalkyl (e.g. trifluoromethyl and the like) or halo. In otherembodiments, R^(11a) and R^(11b) are each independently fluoro, chloro,bromo, cyano or trifluoromethyl.

As generally described above for compounds of formula (I), X is CR⁴ orN. In certain embodiments, X is CR⁴ and R⁴ is as defined in the Summary.In other embodiments, X is CR⁴, and R⁴ is C₁₋₆ alkyl (for example,methyl), haloalkyl, or hydrogen. In still other embodiments, X is CR⁴,and R⁴ is C₁₋₆ alkyl (for example, methyl) or hydrogen. In still otherembodiments, X is CR⁴ and R⁴ is hydrogen. In yet other embodiments, X isN.

As generally described above for compounds of formula (I), R³ ishydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,alkoxyalkyl, hydroxyalkyl, haloalkyl, halo, cyano, or cyanoalkyl; withthe proviso that when n is 1, R¹ is substituted phenyl, X is CR⁴ whereinR⁴ is hydrogen, R² is A³ wherein A³ is pyridinyl or 1,3-thiazolyl, thenR³ is other than hydrogen. In certain embodiments, R³ is C₁₋₆ alkyl(e.g. methyl, ethyl, tert-butyl), halo (e.g. chloro, bromo), optionallysubstituted cycloalkyl (e.g. optionally substituted cyclopropyl),haloalkyl, or hydroxyalkyl (e.g. 2-hydroxyprop-2-yl and the like). Inother embodiments, R³ is C₁₋₆ alkyl (e.g. methyl, ethyl, tert-butyl),halo, or cycloalkyl. In yet other embodiments, R³ is tert-butyl.

As generally described above for compounds of formula (I), R² is—NR^(23a)SO₂R^(105a), —NR^(23b)COR^(105b), —NR^(23b)CO(O)R^(105b),—NR^(23c)CONR^(101a)R^(102a), —NR^(23d)SO₂NR^(101b)R^(102b),—NR^(23e)R²⁴, —SO₂NR^(101c)R^(102c), —OC(O)NR^(101a)R^(102a), A¹, A², orA³; with the proviso that when X is CR⁴, R¹ is substituted phenyl, andR² is —OC(O)NR^(101a)R^(102a) wherein R^(101a) and R^(102a) are eachindependently hydrogen, alkyl, alkoxyalkyl, cycloalkyl, haloalkyl, orhaloalkoxyalkyl, then R¹⁰ is other than haloalkoxyalkoxy,—O—NR^(23f)R^(23g), O—(CR^(25b)R^(26b))_(u)-A⁴,—O—(CR^(25b)R^(26b))_(u)—C(═S)NR^(101d)R^(102d),—O—(CR^(25b)R^(26b))_(u)—C(O)NR^(101d)R^(102d),—O—(CR^(25b)R^(26b))_(u)—SO₂NR^(101d)R^(102d), and—O—(CR^(25b)R^(26b))_(q)—NR¹⁰³R¹⁰⁴.

In certain embodiments, R² is —NR^(23a)SO₂R^(105a),—NR^(23b)CO(O)R^(105b), —NR^(23e)R²⁴, —SO₂NR^(101c)R^(102c), or—OC(O)NR^(101a)R^(102a). In certain embodiments, R² is—NR^(23a)SO₂R^(105a). In other embodiments, R² is—NR^(23b)CO(O)R^(105b). In yet other embodiments, R² is —NR^(23e)R²⁴. Inother embodiments, R² is —SO₂NR^(101c)R^(102c). In yet otherembodiments, R² is —OC(O)NR^(101a)R^(102a). R^(23a), R^(105a), R^(23b),R^(105b), R^(23e), R²⁴, R^(101c), R^(102c), R^(101a), and R^(102a) areas described in the Summary and embodiments herein. In conjunction withany of the above or below embodiments, R^(23a), R^(23b), R^(23e) areeach independently, for example, but not limited thereto, hydrogen, C₁₋₆alkyl (e.g. methyl and the like), or optionally substituted cycloalkyl(e.g. optionally substituted cyclopropyl), particularly hydrogen or C₁₋₆alkyl (e.g. methyl and the like); R^(105a) and R²⁴ are eachindependently, for example, C₁₋₆ alkyl (e.g. methyl, ethyl and the like)or optionally substituted cycloalkyl (e.g. optionally substitutedcyclopropyl), particularly C₁₋₆ alkyl (e.g. methyl, ethyl and the like);R^(105b) is, for example, C₁₋₆ alkyl (e.g. tert-butyl); non-limitingexamples of R^(101a), R^(102a), R^(101c), R^(102c), independent of eachother, include hydrogen, C₁₋₆ alkyl (e.g. methyl, ethyl, tert-butyl andthe like), and optionally substituted cyclopropyl, R^(101a) and R^(102a)together with the nitrogen to which they are attached optionally form a4-7 membered monocyclic heterocycle wherein the monocyclic heterocyclecontains 0 or 1 additional heteroatom, 0 or 1 double bond and isoptionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of alkyl, alkoxy, haloalkyl, halo,hydroxy and oxo; non-limiting examples of such monocyclic heterocyclesinclude azetidinyl, piperidinyl, and piperazinyl, each of which isoptionally substituted as described above.

In another embodiment R² is —NR^(23d)SO₂NR^(101b)R^(102b) whereinR^(23d), R^(101b), and R^(102b) are as defined in formula (I). R^(101b)and R^(102b) independent of each other, may be chosen from the groupconsisting of hydrogen, alkyl, alkoxyalkyl, cycloalkyl, haloalkyl andhaloalkoxyalkyl. Alternatively, R^(101b) and R^(102b) together with thenitrogen to which they are attached form a 4-7 membered monocyclicheterocycle containing 0 or 1 additional heteroatom, 0 or 1 double bond,and is optionally substituted with 1, 2 or 3 substituents independentlyselected from the group consisting of alkyl, alkoxy, haloalkyl, halo,hydroxy, and oxo.

In certain embodiments, R² is A¹, A², or A³.

In certain embodiments, R² is A¹. In other embodiments, R² is A². Incertain embodiments of formula (I), R² is A³.

A¹, A², and A³ have meanings as described in the Summary and herein.

In conjunction with any of the above or below embodiments, non limitingexamples of A¹ include azetidinyl (including, but not limited to,azetidin-3-yl and azetidin-2-yl), pyrrolidinyl (including, but notlimited to, pyrrolidin-2-yl and pyrrolidin-1-yl), piperidinyl(including, but not limited to, piperidin-1-yl, piperidin-2-yl, andpiperidin-3-yl), and imidazolidinyl (including, but not limited to,imidazolidin-1-yl), wherein each of the azetidinyl, pyrrolidinyl,piperidinyl, and imidazolidinyl groups is independently unsubstituted orsubstituted with 1, 2, or 3 groups represented by R^(21a) whereinR^(21a) is as described in the Summary and herein. In certain examplesof A¹, R^(21a) is C₁₋₆ alkyl (e.g. methyl, ethyl, and the like),haloalkyl, oxo, ═S, —C(O)OR^(105d), or —SO₂R^(105c). In certainembodiments of A¹, R^(21a), for example, is C₁₋₆ alkyl (e.g. methyl,ethyl, and the like), haloalkyl (e.g. trifluoromethyl and the like),oxo, ═S, —C(O)OR^(105d), or —SO₂R^(105c) wherein R^(105c) is C₁₋₆ alkyl(e.g. methyl, ethyl, and the like) or optionally substituted cycloalkyl(e.g. optionally substituted cyclopropyl), and R^(105d) is methyl orethyl. In yet other examples of A¹, R^(21a) is methyl, ethyl, oxo, ═S,or —SO₂R^(105c) wherein R^(105c) is methyl, ethyl, or optionallysubstituted cyclopropyl.

In conjunction with any of the above or below embodiments, non limitingexamples of A³ include pyrrolyl (including, but not limited to,1H-pyrrol-1-yl), thiazolyl (including, but not limited to,1,3-thiazol-4-yl, 1,3-thiazol-5-yl, and 1,3-thiazol-2-yl), pyrazolyl(including, but not limited to, pyrazol-5-yl), or pyridinyl (including,but not limited to, pyridin-3-yl), and each A³ is independentlyunsubstituted or substituted with 1, 2 or 3 groups represented byR^(22a) wherein R^(22a) is as described in the Summary and herein. Incertain examples of A³, R^(22a) is halo, C₁₋₆ alkyl (e.g. methyl, ethyl,and the like), or haloalkyl (e.g. trifluoromethyl and the like). Inother examples of A³, R^(22a) is methyl, trifluoromethyl, chloro,fluoro, bromo, or iodo.

As described generally in the Summary, R^(25a) and R^(26a), at eachoccurrence, are each independently hydrogen, alkyl, cyclopropyl,cyclobutyl, cyclopentyl, halo, haloalkyl, or alkoxy; R^(25a) and R^(26a)taken together with the carbon atom to which they are attachedoptionally form a monocyclic ring selected from the group consisting ofcyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; wherein each ofthe cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl isindependently unsubstituted or substituted with 1, 2, 3, 4, 5, or 6substituents independently selected from the group consisting of alkyl,halo, haloalkyl, alkoxy, oxo, hydroxy, cyano, and haloalkoxy. In certainembodiments, R^(25a) or R^(26a), at each occurrence, are eachindependently hydrogen or C₁₋₆ alkyl (e.g. methyl, ethyl, and the like).In other embodiments, R^(25a) and R^(26a), at each occurrence, are eachindependently hydrogen or methyl.

As described generally in the Summary, n is 1, 2, 3, or 4. In certainembodiments, n is 1, 2, or 3. In yet other embodiments, n is 1 or 2.

In certain embodiments, R^(25a) and R^(26a) taken together with thecarbon to which they are attached form a monocyclic ring selected fromthe group consisting of cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl. It will be appreciated that only the R^(25a) and R^(26a)groups that are bound to the same carbon atom may form a ring asdescribed above.

It will be appreciated that when R^(25a) and R^(26a) taken together withthe carbon to which they are attached form a monocyclic ring aspreviously described, and n is 2, 3, or 4, then only one set of R^(25a)and R^(26a) may form a ring with the carbon atom to which they are boundto.

Contemplated herein are compounds of formula (I), (I-A), (I-B), (I-C),(I-D) and (I-E) with combinations of the above embodiments, includingparticular, more particular and preferred embodiments.

For example, within each of the foregoing compounds having formula (I),(I-A), (I-B), (I-C), (I-D), or (I-E), examples of a group include thosewherein X is N.

Examples of another group of compounds having formula (I), (I-A), (I-B),(I-C), (I-D), or (I-E) include those wherein X is CR⁴, and R⁴ is asdescribed generally above and in embodiments described above and herein,with the proviso that in compounds of formula (I), (I-A), (I-B) or(I-C), when R⁴ is hydrogen, n is 1, R¹ is substituted phenyl, R² is A³,and A³ is pyridinyl or 1,3-thiazolyl, then R³ is other than hydrogen.

Within each group of compounds of formula (I), (I-A), (I-B), (I-C),(I-D), or (I-E) as described in the preceding paragraphs, y, z, R¹, R²,R³, R⁴, n, R¹⁰, R^(11a), R^(11b), R^(25a), and R^(26a) are eachdescribed generally above and in embodiments described above and herein.

Thus, of each groups of compounds of formula (I), (I-A), (I-B), (I-C),(I-D), or (I-E) as described in the preceding paragraphs, examples of asubgroup include, but are not limited to, those wherein R² is—NR^(23a)SO₂R^(105a), —NR^(23b)COR^(105b), —NR^(23b)CO(O)R^(105b),—NR^(23c)CONR^(101a)R^(102a), —NR^(23d)SO₂NR^(101b)R^(102b),—NR^(23e)R²⁴, —SO₂NR^(101c)R^(102c), or —OC(O)NR^(101a)R^(102a).

Examples of another subgroup include, but are not limited to, thosewherein R² is —NR^(23a)SO₂R^(105a), —NR^(23b)CO(O)R^(105b),—NR^(23e)R²⁴, —SO₂NR^(101c)R^(102c), or —OC(O)NR^(101a)R^(102a).

Examples of another subgroup include, but are not limited to, thosewherein R² is —NR^(23a)SO₂R^(105a).

Examples of another subgroup include, but are not limited to, thosewherein R² is —NR^(23b)CO(O)R^(105b).

Examples of yet another subgroup include, but are not limited to, thosewherein R² is —NR^(23e)R²⁴.

Examples of yet another subgroup include, but are not limited to, thosewherein R² is —SO₂NR^(101c)R^(102c).

Examples of yet another subgroup include, but are not limited to, thosewherein R² is —OC(O)NR^(101a)R^(102a).

In conjunction with any of the above described groups and subgroups,R^(23a), R^(23b), R^(23c), R^(23d), R^(23e), R²⁴, R^(105a), R^(105b),R^(101a), R^(101b), R^(101c), R^(102a), R^(102b), and R^(102c), are asdescribed generally in the Summary and in embodiments or examplesdescribed above.

Other examples of a subgroup include those wherein R² is A¹, A², or A³.

Yet other examples of a subgroup of formula (I), (I-A), (I-B), (I-C),(I-D), or (I-E) include, but are not limited to, those wherein R² is A¹.

Examples of yet another subgroup of compounds of formula (I), (I-A),(I-B), (I-C), (I-D), or (I-E) include, but are not limited to, thosewherein R² is A².

Examples of still another subgroup of compounds of formula (I), (I-A),(I-B), (I-C), (I-D), or (I-E) include, but are not limited to, thosewherein R² is A³.

In conjunction with any of the three preceeding subgroups A¹, A², and A³have meanings as described generally in the Summary and in embodimentsor examples described above.

Of all examples of the groups and subgroups of compounds of formula (I),(I-A), (I-B), (I-C), (I-D), or (I-E) as discussed herein above, y, z, n,R¹, R³, R⁴, R^(25a), R^(26a), R¹⁰, R^(11a), and R^(11b) are as describedgenerally in the Summary and in embodiments described above. Forexample, R³ is alkyl (such as, but not limited to, methyl, tert-butyl),halo (for example, chloro, bromo), cycloalkyl, haloalkyl, orhydroxyalkyl. In certain embodiments, R³ is alkyl (for example, methyl,tert-butyl), halo, or cycloalkyl. Preferably, R³ is tert-butyl. R⁴, forexample, is hydrogen, alkyl (for example, methyl), or haloalkyl.

Thus, examples of compounds of formula (I), (I-A)-(I-E) include, but arenot limited to, those wherein X is N, R² is —NR^(23a)SO₂R^(105a),—NR^(23b)CO(O)R^(105b), —NR^(23e)R²⁴, —SO₂NR^(101c)R^(102c), or—OC(O)NR^(101a)R^(102a), and R³ is C₁₋₆ alkyl (e.g. methyl, ethyl,tert-butyl, and the like), optionally substituted cycloalkyl (e.g.optionally substituted cyclopropyl), halo (e.g. chloro, bromo),haloalkyl, or hydroxyalkyl (e.g. 2-hydroxyprop-2-yl and the like). R¹,R¹⁰, R^(11a), R^(11b), n, y, z, R^(23a), R^(23b), R^(23e), R²⁴, R^(25a),R^(26a), R^(101a), R^(102a), R^(101c), R^(102c) R^(105a), and R^(105b)have meanings as described generally in the Summary and in embodimentsdescribed above.

Other examples of compounds of formula (I), (I-A)-(I-E) include, but arenot limited to, those wherein X is N, R² is A¹, and R³ is C₁₋₆ alkyl(e.g. methyl, ethyl, tert-butyl, and the like), optionally substitutedcycloalkyl (e.g. optionally substituted cyclopropyl), halo (e.g. chloro,bromo), haloalkyl, or hydroxyalkyl (e.g. 2-hydroxyprop-2-yl and thelike). A¹, R¹, R¹⁰, R^(11a), R^(11b), n, y, z, R^(25a), and R^(26a) havemeanings as described generally in the Summary and in embodimentsdescribed above.

Other examples of compounds of formula (I), (I-A)-(I-E) include, but arenot limited to, those wherein X is N, R² is A³, R³ is C₁₋₆ alkyl (e.g.methyl, ethyl, tert-butyl, and the like), optionally substitutedcycloalkyl (e.g. optionally substituted cyclopropyl), halo (e.g. chloro,bromo), haloalkyl, or hydroxyalkyl (e.g. 2-hydroxyprop-2-yl and thelike). A³, R¹, R¹⁰, R^(11a), R^(11b), n, y, z, R^(25a), and R^(26a) havemeanings as described generally in the Summary and in embodimentsdescribed above.

Yet other examples of compounds of formula (I), (I-A)-(I-E) include, butare not limited to, those wherein X is CR⁴, R² is —NR^(23a)SO₂R^(105a),—NR^(23b)CO(O)R^(105b), —NR^(23e)R²⁴, —SO₂NR^(101c)R^(102c), or—OC(O)NR^(101a)R^(102a), R³ is C₁₋₆ alkyl (e.g. methyl, ethyl,tert-butyl, and the like), optionally substituted cycloalkyl (e.g.optionally substituted cyclopropyl), halo (e.g. chloro, bromo),haloalkyl, or hydroxyalkyl (e.g. 2-hydroxyprop-2-yl and the like), andR⁴ is hydrogen, C₁₋₆ alkyl (e.g. methyl and the like), or haloalkyl. R¹,R¹⁰, R^(11a), R^(11b), n, y, z, R^(23a), R^(23b), R^(23e), R²⁴, R^(25a),R^(26a), R^(101a), R^(102a), R^(101c), R^(102c) R^(105a), and R^(105b)have meanings as described generally in the Summary and in embodimentsdescribed above.

Other examples of compounds of formula (I), (I-A)-(I-E) include, but arenot limited to, those wherein X is CR⁴, R² is A¹, R³ is C₁₋₆ alkyl (e.g.methyl, ethyl, tert-butyl, and the like), optionally substitutedcycloalkyl (e.g. optionally substituted cyclopropyl), halo (e.g. chloro,bromo), haloalkyl, or hydroxyalkyl (e.g. 2-hydroxyprop-2-yl and thelike), and R⁴ is hydrogen, C₁₋₆ alkyl (e.g. methyl and the like), orhaloalkyl. A¹, R¹, R¹⁰, R^(11a), R^(11b), n, y, z, R^(25a), and R^(26a)have meanings as described generally in the Summary and in embodimentsdescribed above.

Other examples of compounds of formula (I), (I-A)-(I-E) include, but arenot limited to, those wherein X is CR⁴, R² is A³, and R³ is C₁₋₆ alkyl(e.g. methyl, ethyl, tert-butyl, and the like), optionally substitutedcycloalkyl (e.g. optionally substituted cyclopropyl), halo (e.g. chloro,bromo), haloalkyl, or hydroxyalkyl (e.g. 2-hydroxyprop-2-yl and thelike), and R⁴ is hydrogen, C₁₋₆ alkyl (e.g. methyl and the like), orhaloalkyl. A³, R¹, R¹⁰, R^(11a), R^(11b), n, y, z, R^(25a), and R^(26a)have meanings as described generally in the Summary and in embodimentsdescribed above.

In conjunction with any groups or subgroups of compounds describedabove, A¹, A³, R¹, R¹⁰, R^(11a), R^(11b), n, y, z, R^(23a), R^(23b),R^(23c), R^(23d), R^(23e), R²⁴, R^(25a), R^(26a), R^(101a), R^(101a),R^(101c), R^(102a), R^(102b), R^(102c) R^(105a), and R^(105b) havemeanings as described generally in the Summary and in embodimentsdescribed above. In certain embodiments, R⁴ is hydrogen or alkyl (forexample, methyl), or haloalkyl. In certain embodiments, R⁴ is hydrogenor alkyl (for example, methyl). In other embodiments, R⁴ is hydrogen.R^(25a) and R^(26a), for example, are hydrogen or C₁₋₆ alkyl (e.g.methyl, ethyl, and the like), and n is 1, 2, 3, or 4. In certainembodiments, R^(25a) and R^(26a), for example, are hydrogen or methyl,and n is 1 or 2.

Exemplary compounds include, but are not limited to:

-   N-[(2Z)-5-tert-butyl-3-{[1-(methylsulfonyl)azetidin-3-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-2-methoxy-5-(trifluoromethyl)benzamide;-   N-[(2Z)-5-tert-butyl-3-{[1-(cyclopropylsulfonyl)azetidin-3-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-2-methoxy-5-(trifluoromethyl)benzamide;-   5-chloro-2-methoxy-N-[(2Z)-5-methyl-3-{[1-(methylsulfonyl)azetidin-3-yl]methyl}-1,3-thiazol-2(3H)-ylidene]benzamide;-   N-[(2Z)-5-tert-butyl-3-{[(2R)-5-oxopyrrolidin-2-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;-   N-[(2Z)-5-tert-butyl-3-{[(2S)-5-oxopyrrolidin-2-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;-   N-[(2Z)-5-tert-butyl-3-{[(2S)-5-oxopyrrolidin-2-yl]methyl}-1,3,4-thiadiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;-   N-[(2Z)-5-tert-butyl-3-{[(2R)-5-oxopyrrolidin-2-yl]methyl}-1,3,4-thiadiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;-   N-[(2Z)-5-tert-butyl-3-{[(2S)-1-methyl-5-oxopyrrolidin-2-yl]methyl}-1,3,4-thiadiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;-   N-[(2Z)-5-tert-butyl-3-{[1-(methylsulfonyl)azetidin-3-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;-   N-[(2Z)-5-tert-butyl-3-{2-[methyl(methylsulfonyl)amino]ethyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;-   N-[(2Z)-5-tert-butyl-3-[2-(dimethylamino)ethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;-   N-[(2Z)-5-tert-butyl-3-{2-[(methylsulfonyl)amino]ethyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;-   N-[(2Z)-5-tert-butyl-3-{2-[(ethylsulfonyl)(methyl)amino]ethyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;-   5-chloro-N-[(2Z)-3-[(6-fluoropyridin-3-yl)methyl]-5-methyl-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide;-   N-[(2Z)-3-[(2R)-azetidin-2-ylmethyl]-5-tert-butyl-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;-   5-chloro-N-[(2Z)-5-chloro-3-(1,3-thiazol-4-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide;-   N-[(2Z)-5-bromo-3-(1,3-thiazol-4-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;-   5-chloro-2-methoxy-N-[(2Z)-5-methyl-3-(1,3-thiazol-4-ylmethyl)-1,3-thiazol-2(3H)-ylidene]benzamide;-   N-[(2Z)-5-tert-butyl-3-(1,3-thiazol-4-ylmethyl)-1,3,4-thiadiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;-   2,5-dichloro-N-[(2Z)-5-methyl-3-[(2-methyl-1,3-thiazol-4-yl)methyl]-1,3-thiazol-2(3H)-ylidene]benzamide;-   5-chloro-2-methoxy-N-[(2Z)-5-methyl-3-[(2-methyl-1,3-thiazol-4-yl)methyl]-1,3-thiazol-2(3H)-ylidene]benzamide;-   5-chloro-2-methoxy-N-[(2Z)-5-methyl-3-(1,3-thiazol-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]benzamide;-   5-chloro-2-methoxy-N-[(2Z)-5-methyl-3-[(4-methyl-1,3-thiazol-2-yl)methyl]-1,3-thiazol-2(3H)-ylidene]benzamide;-   5-chloro-N-[(2Z)-3-[(6-chloropyridin-3-yl)methyl]-5-methyl-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide;-   5-chloro-2-methoxy-N-[(2Z)-5-methyl-3-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-1,3-thiazol-2(3H)-ylidene]benzamide;-   N-[(2Z)-5-tert-butyl-3-(1,3-thiazol-4-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;-   2-ethoxy-N-[(2Z)-5-methyl-3-[3-(1H-pyrrol-1-yl)propyl]-1,3-thiazol-2(3H)-ylidene]benzamide;-   5-chloro-2-methoxy-N-[(2Z)-5-methyl-3-[3-(1H-pyrrol-1-yl)propyl]-1,3-thiazol-2(3H)-ylidene]benzamide;-   N-[(2Z)-5-tert-butyl-3-[(2S)-pyrrolidin-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;-   N-[(2Z)-5-tert-butyl-3-[(2S)-piperidin-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;-   N-[(2Z)-5-tert-butyl-3-[(2R)-piperidin-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;-   N-[(2Z)-5-tert-butyl-3-{[(2S)-1-methylpyrrolidin-2-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;-   N-[(2Z)-5-tert-butyl-3-{[(2S)-1-methylpiperidin-2-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;-   N-[(2Z)-5-tert-butyl-3-{[(2R)-1-methylpiperidin-2-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;-   N-[(2Z)-5-tert-butyl-3-{[(2R)-1-ethylpiperidin-2-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;-   N-[(2Z)-5-tert-butyl-3-[(3R)-piperidin-3-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;-   N-[(2Z)-5-tert-butyl-3-[(2R)-pyrrolidin-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;-   N-[(2Z)-5-tert-butyl-3-[2-(2-oxopyrrolidin-1-yl)ethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;-   N-[(2Z)-5-tert-butyl-3-[2-(2-oxopiperidin-1-yl)ethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;-   N-[(2Z)-5-tert-butyl-3-[2-(2-oxoimidazolidin-1-yl)ethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;-   (Z)—N-(5-tert-butyl-3-(2-sulfamoylethyl)thiazol-2(3H)-ylidene)-2-methoxy-5-(trifluoromethyl)benzamide;-   N-[(2Z)-5-tert-butyl-3-{[1-(methylsulfonyl)azetidin-3-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-5-(trifluoromethyl)benzamide;-   5-chloro-2-methoxy-N-[(2Z)-5-methyl-3-{3-[(methylsulfonyl)amino]propyl}-1,3-thiazol-2(3H)-ylidene]benzamide;-   5-chloro-2-methoxy-N-[(2Z)-5-methyl-3-[2-(4-methyl-1,3-thiazol-5-yl)ethyl]-1,3-thiazol-2(3H)-ylidene]benzamide;-   2-[(tert-butylamino)oxy]-N-[(2Z)-5-tert-butyl-3-{[(2S)-5-oxopyrrolidin-2-yl]methyl}-1,3,4-thiadiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;-   tert-butyl    2-[(2Z)-5-tert-butyl-2-[(5-chloro-2-methoxybenzoyl)imino]-1,3-thiazol-3(2H)-yl]ethylcarbamate;-   N-[(2Z)-5-tert-butyl-3-[2-(methylamino)ethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;-   2-(azetidin-3-yloxy)-N-[(2Z)-5-tert-butyl-3-{[1-(methylsulfonyl)azetidin-3-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;-   5-chloro-N-[(2Z)-3-[(2-fluoropyridin-3-yl)methyl]-5-methyl-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide;-   N-[(2Z)-5-tert-butyl-3-{[(2R)-5-thioxopyrrolidin-2-yl]methyl}-1,3-thiazol-2    (3H)-ylidene]-5-chloro-2-methoxybenzamide;-   N-[(2Z)-5-tert-butyl-3-{[(2R)-5-thioxopyrrolidin-2-yl]methyl}-1,3,4-thiadiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;-   N-[(2Z)-5-tert-butyl-3-{[(2S)-5-oxopyrrolidin-2-yl]methyl}-1,3,4-thiadiazol-2(3H)-ylidene]-2-methoxy-5-(trifluoromethyl)benzamide;-   N-[(2Z)-5-tert-butyl-3-{[(2R)-5-oxopyrrolidin-2-yl]methyl}-1,3,4-thiadiazol-2(3H)-ylidene]-2-methoxy-5-(trifluoromethyl)benzamide;-   N-[(2Z)-5-tert-butyl-3-[(1,3-dimethyl-1H-pyrazol-5-yl)methyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;-   N-[(2Z)-5-tert-butyl-3-{[(2S)-5-oxopyrrolidin-2-yl]methyl}-1,3,4-thiadiazol-2(3H)-ylidene]-2-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}-5-(trifluoromethyl)benzamide;-   N-[(2Z)-5-tert-butyl-3-{[(2S)-5-oxopyrrolidin-2-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-5-(trifluoromethyl)benzamide;-   N-[(2Z)-5-tert-butyl-3-{[(2S)-5-oxopyrrolidin-2-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-2-fluoro-5-(trifluoromethyl)benzamide;-   N-[(2Z)-5-tert-butyl-3-{[(2S)-5-oxopyrrolidin-2-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-2-(pyridin-2-ylmethoxy)-5-(trifluoromethyl)benzamide;-   2-[(2Z)-5-tert-butyl-2-[(5-chloro-2-methoxybenzoyl)imino]-1,3-thiazol-3(2H)-yl]ethyl    carbamate; and-   2-[(2Z)-2-{[2-azetidin-1-yl-5-(trifluoromethyl)benzoyl]imino}-5-tert-butyl-1,3-thiazol-3(2H)-yl]ethyl    azetidine-1-carboxylate.

Compounds described herein may exist as stereoisomers wherein asymmetricor chiral centers are present. These stereoisomers are “R” or “S”depending on the configuration of substituents around the chiral carbonatom. The terms “R” and “S” used herein are configurations as defined inIUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry,Pure Appl. Chem., 1976, 45: 13-30.

The various stereoisomers (including enantiomers and diastereomers) andmixtures thereof of the compounds described are also contemplated.Individual stereoisomers of compounds described may be preparedsynthetically from commercially available starting materials thatcontain asymmetric or chiral centers or by preparation of racemicmixtures followed by resolution of the individual stereoisomer usingmethods that are known to those of ordinary skill in the art. Examplesof resolution are, for example, (i) attachment of a mixture ofenantiomers to a chiral auxiliary, separation of the resulting mixtureof diastereomers by recrystallization or chromatography, followed byliberation of the optically pure product; or (ii) separation of themixture of enantiomers or diastereomers on chiral chromatographiccolumns.

Geometric isomers may exist in the present compounds. All variousgeometric isomers and mixtures thereof resulting from the disposition ofsubstituents around a carbon-carbon double bond, a carbon-nitrogendouble bond, a cycloalkyl group, or a heterocycle group arecontemplated. Substituents around a carbon-carbon double bond or acarbon-nitrogen bond are designated as being of Z or E configuration andsubstituents around a cycloalkyl or a heterocycle are designated asbeing of cis or trans configuration.

It is to be understood that compounds disclosed herein may exhibit thephenomenon of tautomerism.

Thus, the formulae drawings within this specification can represent onlyone of the possible tautomeric or stereoisomeric forms. It is to beunderstood that encompassed herein are any tautomeric or stereoisomericform, and mixtures thereof, and is not to be limited merely to any onetautomeric or stereoisomeric form utilized within the naming of thecompounds or formulae drawings.

c. Biological Data

(i) In Vitro Methods—CB₂ and CB₁ Radioligand Binding Assays:

The CB₁ and CB₂ radioligand binding assays described herein are utilizedto determine the selectivity of compounds for binding to CB₂ relative toCB₁ receptors.

HEK293 cells stably expressing human CB₂ receptors were grown until aconfluent monolayer was formed. Briefly, the cells were harvested andhomogenized in TE buffer (50 mM Tris-HCl, 1 mM MgCl₂, and 1 mM EDTA)using a polytron for 2×10 second bursts in the presence of proteaseinhibitors, followed by centrifugation at 45,000×g for 20 minutes. Thefinal membrane pellet was re-homogenized in storage buffer (50 mMTris-HCl, 1 mM MgCl₂, and 1 mM EDTA and 10% sucrose) and frozen at −78°C. until used. Saturation binding reactions were initiated by theaddition of membrane preparation (protein concentration of 5 μg/well forhuman CB₂) into wells of a deep well plate containing [³H]CP-55,940 (120Ci/mmol, a nonselective CB agonist commercially available from Tocris)in assay buffer (50 mM Tris, 2.5 mM EDTA, 5 mM MgCl₂, and 0.5 mg/mLfatty acid free BSA, pH 7.4). After 90 min incubation at 30° C., bindingreaction was terminated by the addition of 300 μl/well of cold assaybuffer followed by rapid vacuum filtration through a UniFilter-96 GF/Cfilter plates (pre-soaked in 1 mg/mL BSA for 2 hours). The boundactivity was counted in a TopCount using Microscint-20. Saturationexperiments were conducted with twelve concentrations of [³H]CP-55,940ranging from 0.01 to 8 nM. Competition experiments were conducted with0.5 nM [³H]CP-55,940 and five concentrations of displacing ligandsselected from the range of 0.01 nM to 10 μM. The addition of 10 μMunlabeled CP-55,940 (Tocris, Ellisville, Mo.) was used to assessnonspecific binding.

HEK293 cells stably expressing rat CB₂ receptors were grown until aconfluent monolayer was formed. Briefly, the cells were harvested andhomogenized in TE buffer (50 mM Tris-HCl, 1 mM MgCl₂, and 1 mM EDTA)using a polytron for 2×10 second bursts in the presence of proteaseinhibitors, followed by centrifugation at 45,000×g for 20 minutes. Thefinal membrane pellet was re-homogenized in storage buffer (50 mMTris-HCl, 1 mM MgCl₂, and 1 mM EDTA and 10% sucrose) and frozen at −78°C. until used. Saturation binding reactions were initiated by theaddition of membrane preparation (protein concentration of 20 μg/wellfor rat CB₂) into wells of a deep well plate containing [³H]CP-55,940(120 Ci/mmol, a nonselective CB agonist commercially available fromTocris) in assay buffer (50 mM Tris, 2.5 mM EDTA, 5 mM MgCl₂, and 0.5mg/mL fatty acid free BSA, pH 7.4). After 45 min incubation at 30° C.,binding reaction was terminated by the addition of 300 μL/well of coldassay buffer followed by rapid vacuum filtration through a UniFilter-96GF/C filter plates (pre-soaked in 1 mg/mL BSA for 2 hours). The boundactivity was counted in a TopCount using Microscint-20. Saturationexperiments were conducted with twelve concentrations of [³H]CP-55,940ranging from 0.01 to 8 nM. Competition experiments were conducted with0.5 nM [³H]CP-55,940 and five concentrations of displacing ligandsselected from the range of 0.01 nM to 10 μM. The addition of 10 μMunlabeled CP-55,940 (Tocris, Ellisville, Mo.) was used to assessnonspecific binding.

Compounds tested were found to bind to CB₂ receptors with K_(i) of lessthan about 1,000 nM, preferably less than 400 nM, more preferably lessthan 200 nM, and most preferably lower than 100 nM.

HEK293 human CB₁ membranes were purchased from Perkin Elmer. Binding wasinitiated by the addition of membranes (8-12 μg per well) into wells(Scienceware 96-well DeepWell plate, VWR, West Chester, Pa.) containing[³H]CP-55,940 (120 Ci/mmol, Perkin Elmer, Boston, Mass.) and asufficient volume of assay buffer (50 mM Tris, 2.5 mM EDTA, 5 mM MgCl₂,and 0.5 mg/mL fatty acid free BSA, pH 7.4) to bring the total volume to250 μL. After incubation (30° C. for 90 minutes), binding was terminatedby the addition of 300 μL per well of cold assay buffer and rapid vacuumfiltration (FilterMate Cell Harvester, Perkin Elmer, Boston, Mass.)through a UniFilter-96 GF/C filter plate (Perkin Elmer, Boston, Mass.)(pre-soaked in 0.3% PEI at least 3 hours), followed by five washes withcold assay buffer. The bound activity was counted in the TopCount usingMicroscint-20 (both from Perkin Elmer, Boston, Mass.). Competitionexperiments were conducted with 1 nM [³H]CP-55,940 and fiveconcentrations (1 nM to 10 μM) of displacing ligands. The addition of 10μM unlabeled CP-55,940 (Tocris, Ellisville, Mo.) was used to assessnonspecific binding. The compounds tested were found to bind to CB₁receptors with K_(i) of about 10 fold to about 1000 fold higher thanthat for CB₂ receptors. These results demonstrate that the compoundstested preferably bind to CB₂ vs. CB₁ receptors, and therefore areselective ligands for the CB2 receptor.

ii) In Vivo Data Animals

Adult male Sprague-Dawley rats (250-300 g body weight, Charles RiverLaboratories, Portage, Mich.) were used. Animal handling andexperimental protocols were approved by the Institutional Animal Careand Use Committee (IACUC) at Abbott Laboratories. For all surgicalprocedures, animals were maintained under halothane anesthesia (4% toinduce, 2% to maintain), and the incision sites were sterilized using a10% povidone-iodine solution prior to and after surgeries.

Incision Model of Postoperative Pain

A skin incision model of postoperative pain was produced using theprocedures described in Brennan et al., 1996, Pain, 64, 493. All ratswere anesthetized with isofluorane delivered via a nose cone. Right hindpaw incision was performed following sterilization procedures. Theplantar aspect of the left hind paw was placed through a hole in asterile plastic drape. A 1-cm longitudinal incision was made through theskin and fascia of the plantar aspect of the hind paw, starting 0.5 cmfrom the proximal edge of the heel and extending towards the toes, theplantar muscle was elevated and incised longitudinally leaving themuscle origin and insertion points intact. The skin was then closed withtwo mattress sutures (5-0 nylon). After surgery, animals were thenallowed to recover for 2 hours, at which time tactile allodynia wasassessed as described below. To evaluate the anti-nociceptive effects,animals were i.p. administered vehicle or test compound 90 minutesfollowing skin incision and tactile allodynia was assessed 30 minutesafter compound administration.

Tactile allodynia was measured using calibrated von Frey filaments(Stoelting, Wood Dale, Ill.) as described in Chaplan, S. R., F. W. Bach,J. W. Porgrel, J. M. Chung and T. L. Yaksh, 1994, Quantitativeassessment of tactile allodynia in the rat paw, J. Neurosci. Methods,53, 55. Rats were placed into inverted individual plastic cage(20×12.5×20 cm) on top of a suspended wire mesh grid, and acclimated tothe test chambers for 20 minutes. The von Frey filaments were appliedperpendicularly from underneath the cage through openings in the wiremesh floor directly to an area within 1-3 mm (immediately adjacent) ofthe incision, and then held in this position for approximately 8 secondswith enough force to cause a slight bend in the filament. Positiveresponses included an abrupt withdrawal of the hind paw from thestimulus, or flinching behavior immediately following removal of thestimulus. A 50% withdrawal threshold was determined using an up-downprocedure as described in Dixon, W. J., 1980, Efficient analysis ofexperimental observations, Ann. Rev. Pharmacol. Toxicol., 20, 441.

Certain compounds tested in the incision model of postoperative painshowed a statistically significant change in paw withdrawal latencyversus a saline vehicle at less than about 300 micromoles/kg. In a morepreferred embodiment, compounds tested showed efficacy at less thanabout 50 micromoles/kg in the incision model of postoperative pain.

Capsaicin-Induced Secondary Mechanical Hypersensitivity:

Rats were allowed to acclimate to the study room for 1 hour. They werethen briefly restrained, and capsaicin was administered at 10 μg in 10μL of vehicle (10% ethanol and 2-hydroxypropyl cyclodextrin) byintraplantar injection into the center of the right hind paw. Secondarymechanical hyperalgesia was measured at the heel away from the site ofinjection at 180 min following capsaicin (Joshi et al 2006, Neuroscience143, 587-596). Compounds were injected (i.p.) 30 min before testing (150min post-capsaicin).

Tactile allodynia was measured as described above.

Certain compounds that were tested showed a statistically significantchange in paw withdrawal latency versus a saline vehicle at less thanabout 300 micromoles/kg. In a more preferred embodiment, certaincompounds showed efficacy of less than about 50 micromoles/kg.

MIA-Induced Knee Joint Osteoarthritic Pain Model

Unilateral knee joint osteoarthritis was induced in the rats by a singleintra-articular (i.a.) injection of sodium monoiodoacetate (MIA, 3 mg in0.05 mL sterile isotonic saline) into the right knee joint cavity underlight isoflurane anesthesia using a 26G needle. The dose of the MIA (3mg/i.a. injection) was selected based on results obtained frompreliminary studies wherein an optimal pain behavior was observed atthis dose. Pain behavioral assessment of hind limb grip force wereconducted by recording the maximum compressive force exerted on the hindlimb strain gauge setup, in a commercially available grip forcemeasurement system (Columbus Instruments, Columbus, Ohio). The gripforce data was converted to a maximum hindlimb cumulative compressiveforce (CFmax) (gram force)/kg body weight for each animal. The analgesiceffects of test compounds were determined 20 days following the i.a.injection of MIA. The vehicle control group for each compound beingtested was assigned 0% whereas the age matched naïve group was assignedas being 100% (normal). The % effects for each dose group was thenexpressed as % return to normalcy compared to the naïve group. Compoundswere administered either orally (p.o.) or intraperitoneally (i.p.). Theassessment of the analgesic effects of test compounds is typically madeanytime between about 1 hour and about 5 hours following oraladministration. The assessment of the analgesic effects of testcompounds is typically made anytime between about 0.5 hour and about 2hours following i.p. administration. Selection of the preferred timepoints for measuring the analgesic effects of test compounds is basedupon consideration of the individual pharmacokinetic characteristics oftest compounds in the rat. Time points known or expected to providehigher plasma concentrations of test compounds are preferred over thosethat were known or expected to provide lower concentrations. Theassessment of the analgesic effects of test compounds can be madefollowing a single dose or following repeated dosing of test compoundswherein the frequency of dosing is 1 to 2 times daily. The duration ofsuch repeated daily dosing may last for any time greater than one day. Atypical duration of repeated daily dosing is about 5 days to about 12days.

A representative compound of formula (I) tested showed a statisticallysignificant change in hind limb grip force strength versus a salinevehicle at less than about 50 micromoles/kg in the MIA model ofosteoarthritic pain following a single oral dose.

d. Methods of Using the Compounds

One embodiment provides a method for treating pain (for example,inflammatory pain, osteoarthritic pain, neuropathic pain or nociceptivepain) in a mammal (including human) in need of such treatment. Themethod comprises administering to the mammal therapeutically effectiveamount of any of the compounds as described herein, or pharmaceuticallyacceptable salts or solvates thereof. The method further comprisesadministration of compounds described herein as a single dose. Themethod also comprises repeated or chronic administration of presentcompounds over a period of days, weeks, months, or longer. Compoundsdescribed herein may be administered alone, or in combination with oneor more other compounds described herein, or in combination (i.e.co-administered) with one or more additional pharmaceutical agents. Forexample, one or more compound of formula (I), or pharmaceuticallyacceptable salts or solvates thereof, may be administered in combinationwith acetaminophen, or with one or more nonsteroidal anti-inflammatorydrug (NSAID) such as, but not limited to, aspirin, diclofenac,diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen,ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid,mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide,nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam,sulfasalazine, sulindac, tolmetin and zomepirac; or administered with acombination of acetaminophen and one or more NSAID. In certainembodiments, the nonsteroidal anti-inflammatory drug (NSAID) isibuprofen.

Another embodiment provides a method for treating a disorder selectedfrom the group consisting of neurological disorders, cancers of theimmune system, respiratory disorders, and cardiovascular disorders in amammal in need of such treatment. The method comprises administering tothe mammal therapeutically effective amount of one or more of thecompound(s) described herein or pharmaceutically acceptable salts orsolvates thereof.

Yet another embodiment relates to a method for providing neuroprotectionin a mammal in need of such treatment. This method comprisesadministering to the mammal therapeutically effective amount of one ormore compound(s) described herein or pharmaceutically acceptable saltsor solvates thereof.

A further embodiment provides a method of increasing the therapeuticeffectiveness or potency of compounds described herein by repeated orchronic administration of the compound(s) or the pharmaceuticalcomposition over a period of days, weeks, or months.

In addition to the data contained herein, several lines of evidencesupport the assertion that CB₂ receptors play a role in analgesia.HU-308 is one of the first highly selective CB₂ agonists identified thatelicits an antinociceptive response in the rat formalin model ofpersistent pain (Hanus, L., et al., Proc. Nat. Acad. Sci., 1999, 96,14228-14233). The CB₂-selective cannabiniod ligand AM-1241 exhibitsrobust analgesic efficacy in animal models of acute thermal pain (Malan,T. P., et al., Pain, 2001, 93, 239-245; Ibrahim, M. M., et al., Proc.Nat. Acad. Sci., 2005, 102(8), 3093-3098), persistent pain (Hohmann, A.G., et al., J. Pharmacol. Exp. Ther., 2004, 308, 446-453), inflammatorypain (Nackley, A. G., et al., Neuroscience, 2003, 119, 747-757;Quartilho, A. et al., Anesthesiology, 2003, 99, 955-60), and neuropathicpain (Ibrahim, M. M., et al., Proc. Nat. Acad. Sci., 2003, 100,10529-10533). The CB₂-selective partial agonist GW405833, also known asL768242, is efficacious in rodent models of neuropathic, incisional, andboth chronic and acute inflammatory pain (Valenzano, K. J., et al.,Neuropharmacology, 2005, 48, 658-672 and Clayton, N., et al., Pain,2002, 96, 253-260).

The potential exists for CB₂ modulators to have opioid sparing effects.A synergy between the analgesic effects of morphine and the nonselectiveCB agonist Δ⁹-THC has been documented (Cichewicz, D. L., Life Sci. 2004,74, 1317-1324). Therefore, CB₂ ligands have additive or synergisticanalgesic effects when used in combination with lower doses of morphineor other opioids, providing a strategy for reducing adverse opioidevents, such as tolerance, constipation, and respiratory depression,without sacrificing analgesic efficacy.

CB₂ receptors are present in tissues and cell types associated withimmune functions and CB₂ receptor mRNA is expressed by human B cells,natural killer cells, monocytes, neutrophils, and T cells (Galiegue etal., Eur. J. Biochem., 1995, 232, 54-61). Studies with CB₂ knockout micehave suggested a role for CB₂ receptors in modulating the immune system(Buckley, N. E., et al., Eur. J. Pharmacol. 2000, 396, 141-149).Although immune cell development and differentiation are similar inknockout and wild type animals, the immunosuppressive effects of Δ⁹-THCare absent in the CB₂ receptor knockout mice, providing evidence for theinvolvement of CB₂ receptors in immunomodulation. As such, selective CB₂modulators may be useful for the treatment of autoimmune diseasesincluding but not limited to multiple sclerosis, rheumatoid arthritis,systemic lupus, myasthenia gravis, type I diabetes, irritable bowelsyndrome, psoriasis, psoriatic arthritis, and hepatitis; and immunerelated disorders including but not limited to tissue rejection in organtransplants, gluten-sensitive enteropathy (Celiac disease), asthma,chronic obstructive pulmonary disease, emphysema, bronchitis, acuterespiratory distress syndrome, allergies, allergic rhinitis, dermatitis,and Sjogren's syndrome.

Microglial cells are considered to be the immune cells of the centralnervous system (CNS) where they regulate the initiation and progressionof immune responses. CB₂ receptor expression on microglia is dependentupon inflammatory state with higher levels of CB₂ found in primed,proliferating, and migrating microglia relative to resting or fullyactivated microglial (Carlisle, S. J., et al. Int. Immunopharmacol.,2002, 2, 69). Neuroinflammation induces many changes in microglia cellmorphology and there is an upregulation of CB₂ receptors and othercomponents of the endocannabinoid system.—Neuroinflammation occurs inseveral neurodegenerative diseases, and induction of microglial CB₂receptors has been observed (Carrier, E. J., et al., Current DrugTargets—CNS & Neurological Disorders, 2005, 4, 657-665). Thus, CB₂ligands may be clinically useful for the treatment of neuroinflammation.

Multiple sclerosis is common immune-mediated disease of the CNS in whichthe ability of neurons to conduct impulses becomes impaired throughdemyelination and axonal damage. The demyelination occurs as aconsequence of chronic inflammation and ultimately leads to a broadrange of clinical symptoms that fluctuate unpredictably and generallyworsen with age. These include painful muscle spasms, tremor, ataxia,motor weakness, sphincter dysfunction, and difficulty speaking (Pertwee,R. G., Pharmacol. Ther. 2002, 95, 165-174). The CB₂ receptor isup-regulated on activated microglial cells during experimentalautoimmune encephalomyelitis (EAE) (Maresz, K., et al., J. Neurochem.2005, 95, 437-445). CB₂ receptor activation prevents the recruitment ofinflammatory cells such as leukocytes into the CNS (Ni, X., et al.,Multiple Sclerosis, 2004, 10, 158-164) and plays a protective role inexperimental, progressive demyelination (Arevalo-Martin, A.; et al., J.Neurosci., 2003, 23(7), 2511-2516), which are critical features in thedevelopment of multiple sclerosis. Thus, CB₂ receptor modulators mayprovide a unique treatment for demyelinating pathologies.

Alzheimer's disease is a chronic neurodegenerative disorder accountingfor the most common form of elderly dementia. Recent studies haverevealed that CB₂ receptor expression is upregulated in neuriticplaque-associated microglia from brains of Alzheimer's disease patients(Benito, C., et al., J. Neurosci., 2003, 23(35), 11136-11141). In vitro,treatment with the CB₂ agonist JWH-133 abrogated β-amyloid-inducedmicroglial activation and neurotoxicity, effects that can be blocked bythe CB₂ antagonist SR144528 (Ramirez, B. G., et al., J. Neurosci. 2005,25(8), 1904-1913). CB₂ modulators may possess both anti-inflammatory andneuroprotective actions and thus have clinical utility in treatingneuroinflammation and in providing neuroprotection associated with thedevelopment of Alzheimer's disease.

Increased levels of epithelial CB₂ receptor expression are observed inhuman inflammatory bowel disease tissue (Wright, K., et al.,Gastroenterology, 2005, 129, 437-453). Activation of CB₂ receptorsre-established normal gastrointestinal transit after endotoxicinflammation was induced in rats (Mathison, R., et al., Br. J.Pharmacol. 2004, 142, 1247-1254). CB₂ receptor activation in a humancolonic epithelial cell line inhibited TNF-α-induced interleukin-8(IL-8) release (Ihenetu, K. et al., Eur. J. Pharmacol. 2003, 458,207-215). Chemokines released from the epithelium, such as theneutrophil chemoattractant IL-8, are upregulated in inflammatory boweldisease (Warhurst, A. C., et al., Gut, 1998, 42, 208-213). Thus,administration of CB₂ receptor modulators may represent a novel approachfor the treatment of inflammation and disorders of the gastrointestinaltract including but not limited to inflammatory bowel disease, irritablebowel syndrome, secretory diarrhea, ulcerative colitis, Crohn's diseaseand gastroesophageal reflux disease (GERD).

Hepatic fibrosis occurs as a response to chronic liver injury andultimately leads to cirrhosis, which is a major worldwide health issuedue to the severe accompanying complications of portal hypertension,liver failure, and hepatocellular carcinoma (Lotersztajn, S., et al.,Annu. Rev. Pharmacol. Toxicol., 2005, 45, 605-628). Although CB₂receptors were not detectable in normal human liver, CB₂ receptors wereexpressed liver biopsy specimens from patients with cirrhosis.Activation of CB₂ receptors in cultured hepatic myofibroblasts producedpotent antifibrogenic effects (Julien, B., et al., Gastroenterology,2005, 128, 742-755). In addition, CB₂ knockout mice developed enhancedliver fibrosis after chronic administration of carbon tetrachloriderelative to wild-type mice. Administration of CB₂ receptor modulatorsmay represent a unique approach for the treatment of liver fibrosis.

Cough is a dominant and persistent symptom of many inflammatory lungdiseases, including asthma, chronic obstructive pulmonary disease, viralinfections, and pulmonary fibrosis (Patel, H. J., et al., Brit. J.Pharmacol., 2003, 140, 261-268). Recent studies have provided evidencefor the existence of neuronal CB₂ receptors in the airways, and havedemonstrated a role for CB₂ receptor activation in cough suppression(Patel, H. J., et al., Brit. J. Pharmacol., 2003, 140, 261-268 andYoshihara, S., et al., Am. J. Respir. Crit. Care Med., 2004, 170,941-946). Both exogenous and endogenous cannabinoid ligands inhibit theactivation of C-fibers via CB₂ receptors and reduce neurogenicinflammatory reactions in airway tissues (Yoshihara, S., et al., J.Pharmacol. Sci. 2005, 98(1), 77-82; Yoshihara, S., et al., Allergy andImmunology, 2005, 138, 80-87). Thus, CB₂-selective modulators may haveutility as antitussive agents for the treatment of pulmonaryinflammation, chronic cough, and a variety of airway inflammatorydiseases including but not limited to asthma, chronic obstructivepulmonary disease, and pulmonary fibrosis.

There is a substantial genetic contribution to bone mass density and theCB₂ receptor gene is associated with human osteoporosis (Karsak, M., etal., Human Molecular Genetics, 2005, 14(22), 3389-3396). Osteoclasts andosteoblasts are largely responsible for maintaining bone structure andfunction through a process called remodeling, which involves resorptionand synthesis of bone (Boyle, W. J., et al., Nature, 2003, 423,337-342). CB₂ receptor expression has been detected on osteoclasts andosteoblastic precursor cells, and administration of a CB₂ agonist inmice caused a dose-dependent increase in bone formation (Grotenhermen,F. and Muller-Vahl, K., Expert Opin. Pharmacother., 2003, 4(12),2367-2371). Cannabinoid inverse agonists, including the CB₂-selectiveinverse agonist SR144528, have been shown to inhibit osteoclast activityand reverse ovariectomy-induced bone loss in mice, which is a model forpost-menopausal osteoporosis (Ralston, S. H., et al., Nature Medicine,2005, 11, 774-779). Thus, CB₂ modulators may be useful for the treatmentand prevention of osteoporosis, osteoarthritis, and bone disorders.

Artherosclerosis is a chronic inflammatory disease and is a leadingcause of heart disease and stroke. CB₂ receptors have been detected inboth human and mouse atherosclerotic plaques. Administration of lowdoses of THC in apolipoprotein E knockout mice slowed the progression ofatherosclerotic lesions, and these effects were inhibited by theCB₂-selective antagonist SR144528 (Steffens, S., et al., Nature, 2005,434, 782-786). Thus, compounds with activity at the CB₂ receptor may beclinically useful for the treatment of atheroscelorsis.

CB₂ receptors are expressed on malignant cells of the immune system andtargeting CB₂ receptors to induce apoptosis may constitute a novelapproach to treating malignancies of the immune system. Selective CB₂agonists induce regression of malignant gliomas (Sanchez, C., et al.,Cancer Res., 2001, 61, 5784-5789), skin carcinomas (Casanova, M. L., etal., J. Clin. Invest., 2003, 111, 43-50), and lymphomas (McKallip, R.J., et al., Blood, 2002, 15(2), 637-634). Thus, CB₂ modulators may haveutility as anticancer agents against tumors of immune origin.

Activation of CB₂ receptors has been demonstrated to protect the heartagainst the deleterious effects of ischemia and reperfusion (Lepicier,P., et al., Brit. J. Pharm. 2003, 139, 805-815; Bouchard, J.-F., et al.,Life Sci. 2003, 72, 1859-1870; Filippo, C. D., et al., J. Leukoc. Biol.2004, 75, 453-459). Thus, CB₂ modulators may have utility for thetreatment or prophylaxis of cardiovascular disease and the developmentof myocardial infarction.

Actual dosage levels of active ingredients in the pharmaceuticalcompositions can be varied so as to obtain an amount of the activecompound(s) that is effective to achieve the desired therapeuticresponse for a particular patient, compositions and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the duration oftreatment, the severity of the condition being treated and the conditionand prior medical history of the patient being treated. However, it iswithin the skill of the art to start doses of the compound at levelslower than required to achieve the desired therapeutic effect and togradually increase the dosage until the desired effect is achieved. Inthe treatment of certain medical conditions, repeated or chronicadministration of compounds may be required to achieve the desiredtherapeutic response. “Repeated or chronic administration” refers to theadministration of compounds daily (i.e., every day) or intermittently(i.e., not every day) over a period of days, weeks, months, or longer.In particular, the treatment of chronic painful conditions isanticipated to require such repeated or chronic administration of thecompounds. Compounds described herein may become more effective uponrepeated or chronic administration such that the therapeuticallyeffective doses on repeated or chronic administration may be lower thanthe therapeutically effective dose from a single administration.

Combination therapy includes administration of a single pharmaceuticaldosage formulation containing one or more of the compounds describedherein and one or more additional pharmaceutical agents, as well asadministration of the compounds and each additional pharmaceuticalagent, in its own separate pharmaceutical dosage formulation. Forexample, a compound described herein and one or more additionalpharmaceutical agents, may be administered to the patient together, in asingle oral dosage composition having a fixed ratio of each activeingredient, such as a tablet or capsule; or each agent may beadministered in separate oral dosage formulations.

Where separate dosage formulations are used, present compounds and oneor more additional pharmaceutical agents may be administered atessentially the same time (e.g., concurrently) or at separatelystaggered times (e.g., sequentially).

Compounds described herein can also be administered as a pharmaceuticalcomposition comprising the compounds of interest in combination with oneor more pharmaceutically acceptable carriers. The phrase“therapeutically effective amount” of the present compounds meanssufficient amounts of the compounds to treat disorders, at a reasonablebenefit/risk ratio applicable to any medical treatment. It will beunderstood, however, that the total daily usage of the compounds andcompositions will be decided by the attending physician within the scopeof sound medical judgment. The specific therapeutically effective doselevel for any particular patient will depend upon a variety of factorsincluding the disorder being treated and the severity of the disorder;activity of the specific compound employed; the specific compositionemployed; the age, body weight, general health, sex and diet of thepatient; the time of administration, route of administration, and rateof excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or coincidental with the specificcompound employed; and like factors well-known in the medical arts. Forexample, it is well within the skill of the art to start doses of thecompound at levels lower than required to achieve the desiredtherapeutic effect and to gradually increase the dosage until thedesired effect is achieved.

The total daily dose of the compounds administered to a human or otheranimal range from about 0.01 mg/kg body weight to about 100 mg/kg bodyweight. More preferable doses can be in the range of from about 0.03mg/kg body weight to about 30 mg/kg body weight. If desired, theeffective daily dose can be divided into multiple doses for purposes ofadministration. Consequently, single dose compositions may contain suchamounts or submultiples thereof to make up the daily dose. It isunderstood that the effective daily dose may vary with the duration ofthe treatment.

e. Pharmaceutical Compositions

Pharmaceutical compositions comprise compounds described herein orpharmaceutically acceptable salts or solvates thereof are alsodescribed. The pharmaceutical compositions comprising compoundsdescribed herein may be formulated together with one or more non-toxicpharmaceutically acceptable carriers.

Another aspect relates to pharmaceutical compositions comprising presentcompounds, or pharmaceutically acceptable salts or solvates thereof, andone or more pharmaceutically acceptable carriers, alone or incombination with one or more nonsteroidal anti-inflammatory drug(NSAID), or other analgesics (for example, acetaminophen), orcombinations thereof.

The pharmaceutical compositions can be administered to humans and othermammals orally, rectally, parenterally, intracisternally,intravaginally, intraperitoneally, topically (as by powders, ointmentsor drops), bucally or as an oral or nasal spray. The term “parenterally”as used herein, refers to modes of administration which includeintravenous, intramuscular, intraperitoneal, intrasternal, subcutaneousand intraarticular injection and infusion.

The term “pharmaceutically acceptable carrier” as used herein, means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as, but not limited to, lactose, glucose andsucrose; starches such as, but not limited to, corn starch and potatostarch; cellulose and its derivatives such as, but not limited to,sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients such as, but notlimited to, cocoa butter and suppository waxes; oils such as, but notlimited to, peanut oil, cottonseed oil, safflower oil, sesame oil, oliveoil, corn oil and soybean oil; glycols; such a propylene glycol; esterssuch as, but not limited to, ethyl oleate and ethyl laurate; agar;buffering agents such as, but not limited to, magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as, but not limitedto, sodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

Pharmaceutical compositions for parenteral injection comprisepharmaceutically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions as well as sterile powders forreconstitution into sterile injectable solutions or dispersions justprior to use. Examples of suitable aqueous and nonaqueous carriers,diluents, solvents or vehicles include water, ethanol, polyols (such asglycerol, propylene glycol, polyethylene glycol and the like), vegetableoils (such as olive oil), injectable organic esters (such as ethyloleate) and suitable mixtures thereof. Proper fluidity can bemaintained, for example, by the use of coating materials such aslecithin, by the maintenance of the required particle size in the caseof dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms can be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid and the like. It may also be desirableto include isotonic agents such as sugars, sodium chloride and the like.Prolonged absorption of the injectable pharmaceutical form can bebrought about by the inclusion of agents which delay absorption such asaluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This can be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound may be mixed with at least one inert, pharmaceuticallyacceptable excipient or carrier, such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol and silicic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate and mixturesthereof. In the case of capsules, tablets and pills, the dosage form mayalso comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such carriers as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike.

The solid dosage forms of tablets, dragees, capsules, pills and granulescan be prepared with coatings and shells such as enteric coatings andother coatings well-known in the pharmaceutical formulating art. Theymay optionally contain opacifying agents and may also be of acomposition such that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned carriers.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan andmixtures thereof.

Besides inert diluents, the oral compositions may also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds withsuitable non-irritating carriers or carriers such as cocoa butter,polyethylene glycol or a suppository wax which are solid at roomtemperature but liquid at body temperature and therefore melt in therectum or vaginal cavity and release the active compound.

The compounds can also be administered in the form of liposomes. As isknown in the art, liposomes are generally derived from phospholipids orother lipid substances. Liposomes are formed by mono- or multi-lamellarhydrated liquid crystals which are dispersed in an aqueous medium. Anynon-toxic, physiologically acceptable and metabolizable lipid capable offorming liposomes can be used. The present compositions in liposome formcan contain, in addition to compounds described herein, stabilizers,preservatives, excipients and the like. The preferred lipids are naturaland synthetic phospholipids and phosphatidyl cholines (lecithins) usedseparately or together.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y. (1976), p. 33 et seq.

Dosage forms for topical administration of compounds described hereininclude powders, sprays, ointments and inhalants. The active compoundsmay be mixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers or propellants which maybe required. Ophthalmic formulations, eye ointments, powders andsolutions are also contemplated as being within the scope.

The compounds can be used in the form of pharmaceutically acceptablesalts derived from inorganic or organic acids. The phrase“pharmaceutically acceptable salt” means those salts which are, withinthe scope of sound medical judgment, suitable for use in contact withthe tissues of humans and lower animals without undue toxicity,irritation, allergic response and the like and are commensurate with areasonable benefit/risk ratio.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge et al. describe pharmaceutically acceptable saltsin detail in (J. Pharmaceutical Sciences, 1977, 66: 1 et seq). The saltscan be prepared in situ during the final isolation and purification ofthe compounds or separately by reacting a free base function with asuitable organic acid. Representative acid addition salts include, butare not limited to acetate, adipate, alginate, citrate, aspartate,benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate (isothionate), lactate, malate,maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate,palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate,pivalate, propionate, succinate, tartrate, thiocyanate, phosphate,glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, thebasic nitrogen-containing groups can be quaternized with such agents aslower alkyl halides such as, but not limited to, methyl, ethyl, propyl,and butyl chlorides, bromides and iodides; dialkyl sulfates likedimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides suchas, but not limited to, decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides; arylalkyl halides like benzyl and phenethylbromides and others. Water or oil-soluble or dispersible products arethereby obtained. Examples of acids which can be employed to formpharmaceutically acceptable acid addition salts include such inorganicacids as hydrochloric acid, hydrobromic acid, sulfuric acid, andphosphoric acid and such organic acids as acetic acid, fumaric acid,maleic acid, 4-methylbenzenesulfonic acid, succinic acid and citricacid.

Basic addition salts can be prepared in situ during the final isolationand purification of compounds by reacting a carboxylic acid-containingmoiety with a suitable base such as, but not limited to, the hydroxide,carbonate or bicarbonate of a pharmaceutically acceptable metal cationor with ammonia or an organic primary, secondary or tertiary amine.Pharmaceutically acceptable salts include, but are not limited to,cations based on alkali metals or alkaline earth metals such as, but notlimited to, lithium, sodium, potassium, calcium, magnesium and aluminumsalts and the like and nontoxic quaternary ammonia and amine cationsincluding ammonium, tetramethylammonium, tetraethylammonium,methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine,ethylamine and the like. Other representative organic amines useful forthe formation of base addition salts include ethylenediamine,ethanolamine, diethanolamine, piperidine, piperazine and the like.

The term “pharmaceutically acceptable prodrug” or “prodrug” as usedherein, represents those prodrugs of the compounds which are, within thescope of sound medical judgment, suitable for use in contact with thetissues of humans and lower animals without undue toxicity, irritation,allergic response, and the like, commensurate with a reasonablebenefit/risk ratio, and effective for their intended use.

Contemplated also are compounds formed by synthetic means or formed byin vivo biotransformation of a prodrug.

Compounds described herein can exist in unsolvated as well as solvatedforms, including hydrated forms, such as hemi-hydrates. In general, thesolvated forms, with pharmaceutically acceptable solvents such as waterand ethanol among others are equivalent to the unsolvated forms.

f. General Synthesis

Encompassed herein are compounds prepared by synthetic processes or bymetabolic processes. Preparation of the compounds by metabolic processesincludes those occurring in the human or animal body (in vivo) orprocesses occurring in vitro.

Compounds described herein can be prepared by a variety of processeswell known for the preparation of compounds of this class. For example,the compounds of formula (I) wherein the groups X, n, R¹, R², R³, R⁴,R^(21a), R^(25a), R^(26a), R^(101a), R^(102a), R^(101d), R^(102d),R^(105a), R^(105b), and R¹⁰⁵ have the meanings as set forth in thesummary section unless otherwise noted, can be prepared by generalprocedures such as, but not limited to, those outlined in Schemes 1-9.

As used in the descriptions of the schemes and the examples, certainabbreviations are intended to have the following meanings: HPLC for highperformance liquid chromatography or high pressure liquidchromatography, Boc for tert-butoxycarbonyl, DBU for1,8-diazabicyclo[5.4.0]undec-7-ene; DMSO for dimethylsulfoxide, OMs ormesylate for methanesulfonate, and OTs or tosylate forp-toluenesulfonate.

Compounds of formula (3) may be prepared according to the sequenceoutlined in Scheme 1. Carbonyl compounds (1) can be reacted at roomtemperature with amino compounds (2) in a suitable solvent such as, butnot limited to, acetonitrile, tetrahydrofuran, or dichloromethane for aperiod of about 1 hour to about 24 hours in the presence of adehydrating agent such as, but not limited to, 4 Å molecular sieves;followed by the addition of potassium thiocyanate and iodine withheating at about 50° C. for a period of about 4 hours to about 24 hoursto provide the compounds (3).

Compounds of general formula (4) can be converted to the compounds offormula (I) as outlined in Scheme 2 by reaction with an acid chloride(R¹COCl) or carboxylic acid (R¹CO₂H) under appropriate conditions. Forexample, intermediates (4) can be reacted with R¹COCl in a solvent suchas, but not limited to, tetrahydrofuran, dimethylformamide, ordichloromethane at a temperature from about 25° C. to about 50° C. inthe presence of a base such as, but not limited to, triethylamine,diisopropylethylamine, or potassium carbonate, and optionally in thepresence of a catalyst such as 4-dimethylaminopyridine. Alternatively,intermediates (4) can be reacted with R¹CO₂H in a solvent such as, butnot limited to, tetrahydrofuran or dimethylformamide, in the presence ofa coupling reagent such as 1,1′-carbonyldiimidazole (CDI),bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPCl),1,3-dicyclohexylcarbodiimide (DCC), polymer supported1,3-dicyclohexylcarbodiimide (PS-DCC),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU),O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU), or 1-propanephosphonic acid cyclic anhydride, and in thepresence or absence of a coupling auxiliary such as, but not limited to,1-hydroxy-7-azabenzotriazole (HOAT), or 1-hydroxybenzotriazole hydrate(HOBT). The reaction is generally conducted in the presence or absenceof a base such as, but not limited to, N-methyl morpholine,triethylamine, or diisopropylethylamine.

Compounds (4) may be prepared using the sequence outlined in Scheme 3.Amino compounds of formula (5) can be reacted with compounds of formulaR²—(CR^(25a)R^(26a))_(n)—X²⁰¹, wherein X²⁰¹ is Cl, Br, I, OTs, or OMs,to form compounds (4). This reaction may be performed either neat or ina solvent such as, but not limited to, tetrahydrofuran,dimethylformamide, dimethylsulfoxide, or dioxane, at about roomtemperature or up to about 150° C., and optionally in the presence of acatalyst such as, but not limited to, tetrabutylammonium iodide orsodium iodide. In certain cases, it may be beneficial to conduct thisreaction in the presence of a base such as, but not limited to,triethylamine, potassium carbonate, potassium tert-butoxide, or sodiumhydride.

Compounds of formula (7) wherein n′ is 0, 1, 2, 3, or 4, may be preparedaccording to the sequence outlined in Scheme 4. Carbonyl compounds (1)can be reacted at room temperature with amino compounds (6) using thereaction conditions outlined in Scheme 1 for the conversion of (1) to(3), to provide intermediates (7).

Using the methods provided above in Scheme 2 for the conversion of theintermediates (4) to compounds of formula (I), intermediates (8) whereinn′ is 0, 1, 2, 3, or 4, can be converted to compounds (9) as outlined inScheme 5.

Amine compounds of formulae (10) and (11) may be prepared according tothe sequence outlined in Scheme 6. Compounds (9) wherein n′ is 0, 1, 2,3, or 4, can be converted to compounds (10) by treatment with an acidsuch as, but not limited to, trifluoroacetic acid or hydrochloric acid,in a solvent such as but not limited to dichloromethane at temperaturesranging from about 0° C. to about room temperature. Amine compounds (10)can be converted to amine compounds (11) wherein R^(21a) is alkyl byreactions known in the art. For example, the conversion can be achievedvia reductive amination reaction with a suitable aldehyde or ketone inthe presence of a reducing agent such as sodium triacetoxyhydroborate orsodium cyanoborohydride, in a solvent such as acetonitrile and the like.When treated with reagents of formula ClSO₂R^(105c) in a solvent suchas, but not limited to, tetrahydrofuran or dichloromethane, and in thepresence of a base such as triethylamine, diisopropylethylamine, or DBU,at a temperature ranging from about 0° C. to about room temperature,compound (10) can be transformed into compounds (11) wherein R^(21a) isSO₂R^(105c).

Similarly compounds (10) can be reacted with reagents such asClCOR^(105d) (wherein R^(105d) is other than hydrogen), ClC(O)OR^(105c),ClCONR^(101d)R^(102d), and O═C═NR^(101d) to provide compounds (11)wherein R^(21a) is COR^(105d) (wherein R^(105d) is other than hydrogen),C(O)OR^(105c), and CONR^(101d)R^(102d) respectively.

Compounds of formula (I) may also be prepared according to the sequenceoutlined in Scheme 7. Compounds (5) can be converted to compounds (12)using the conditions described in Scheme 2 for the conversion ofcompounds (4) to compounds of formula (I). Compounds (12) can beconverted to compounds of formula (I) using conditions similar to thosedescribed in Scheme 3 for the conversion of compounds (5) to compounds(4). Compounds (12) can also be converted to compounds of formula (I)using phase transfer conditions, for example: refluxing of compound (12)with compounds of formula R²(CR^(25a)R^(26a))_(n)—X²⁰¹, wherein X²⁰¹ isCl, Br, I, OTs, or OMs in toluene, in the presence of a base likepotassium carbonate. Examples of phase transfer agents include, but arenot limited to, tetrabutylammonium iodide, tetrabutylammoniumhydrogensulfate, tetraethylammonium iodide, and the like.

Compounds of formula (15), (16), (17) and (18) may be prepared accordingto the sequences outlined in Scheme 8. Compounds (13) can be convertedto compounds (14) by reaction with a reagent R²⁰¹—X²⁰¹, wherein R²⁰¹ isR^(23a), R^(23b), or R^(23c) (each of which is independently alkyl,haloalkyl, alkoxyalkyl, or haloalkoxyalkyl), and X²⁰¹ is Cl, Br, I, OTs,or OMs, in solvents such as, but not limited to, tetrahydrofuran, ordimethylformamide, and in the presence of a base such as, but notlimited to, sodium hydride, potassium carbonate, or potassiumtert-butoxide. Compounds (14) can be transformed to compounds (15) bytreatment with an acid such as, but not limited to, trifluoroacetic acidor hydrochloric acid, in solvents such as, but not limited to,dichloromethane at temperatures ranging from about 0° C. to about roomtemperature.

Compounds (13) can be transformed to compounds (17) by removal of theBoc protecting group using similar conditions to those described for theconversion of compounds (14) to compounds (15).

Compounds (15) and (17) can be converted to compounds (16) and (18)wherein R²⁰² is —SO₂R^(105a), respectively, by treatment with reagentsClSO₂R^(105a) in a solvent such as, but not limited to, tetrahydrofuranor dichloromethane, in the presence of a base such as triethylamine,diisopropylethylamine, or DBU, at a temperature ranging from about 0° C.to about room temperature.

Similarly, compounds (15) and (17) can be converted to compounds (16)and (18) wherein R²⁰² is —COR^(105b), —C(O)OR^(105b), or—CONR^(101a)R^(102a), respectively, by reacting with reagents such asClCOR^(105b), ClC(O)OR^(105b), ClCONR^(101a)R^(102a), or O═C═NR^(101a).

Compounds of formula (I-A), wherein y is 0, 1, or 2; R², R³, R^(25a),R^(26a), R^(11a), X, and n are as defined in formula (I); and R¹⁰ isalkoxy, alkoxyalkoxy, haloalkoxy, haloalkoxyalkoxy, —O—NR^(23f)R^(23g),—O—(CR^(25b)R^(26b))_(u)-A⁴,—O—(CR^(25b)R^(26b))_(u)—C(═O)NR^(101d)R^(102d),—O—(CR^(25b)R^(26b))_(u)—C(═S)NR^(101d)R^(102d),—O—(CR^(25b)R^(26b))_(u)—SO₂NR^(101d)R^(102d),—O—(CR^(25b)R^(26b))_(q)—NR¹⁰³R¹⁰⁴, —NR^(23f)R^(23g),—NR^(23f)—(CR^(25b)R^(26b))_(u)-A⁴,—NR^(23f)—(CR^(25b)R^(26b))_(u)—C(═O)NR^(101d)R^(102d),—NR²³—(CR^(25b)R^(26b))_(u)—C(═S)NR^(101d)R^(102d),—NR^(23f)—(CR^(25b)R^(26b))_(u)—SO₂NR^(101d)R^(102d), or—NR²³—(CR^(25b)R^(26b))_(q)—NR¹⁰³R¹⁰⁴ can be prepared from compounds offormula (19). The reaction may be conducted by reacting compounds (19)with an appropriate amine or alcohol reagent in the presence of a basesuch as, but not limited to, triethylamine, potassium tert-butoxide,sodium tert-butoxide or sodium hydride in a solvent such as, but notlimited to, tetrahydrofuran or dimethylformamide at temperatures from 0°C. to 150° C. This reaction may be assisted by microwave irradiation.

It will be appreciated that the synthetic schemes and specific examplesas illustrated in the Examples section are illustrative and are not tobe read as limiting the scope as it is defined in the appended claims.All alternatives, modifications, and equivalents of the syntheticmethods and specific examples are included within the scope of theclaims.

Optimum reaction conditions and reaction times for each individual stepmay vary depending on the particular reactants employed and substituentspresent in the reactants used. Unless otherwise specified, solvents,temperatures and other reaction conditions may be readily selected byone of ordinary skill in the art. Specific procedures are provided inthe Examples section. Reactions may be worked up in the conventionalmanner, e.g. by eliminating the solvent from the residue and furtherpurified according to methodologies generally known in the art such as,but not limited to, crystallization, distillation, extraction,trituration and chromatography. Unless otherwise described, the startingmaterials and reagents are either commercially available or may beprepared by one skilled in the art from commercially available materialsusing methods described in the chemical literature.

The skilled artisan will also appreciate that not all of thesubstituents in the compounds of formula (I) will tolerate certainreaction conditions employed to synthesize the compounds. Routineexperimentations, including appropriate manipulation of the reactionconditions, reagents and sequence of the synthetic route, protection ofany chemical functionality that may not be compatible with the reactionconditions, and deprotection at a suitable point in the reactionsequence of the method, followed by further transformation of themolecules using standard chemical techniques well known to those skilledin the art such as alkylation, acylation, reductive amination,sulfonylation, oxidation, reduction and the like, are included withinthe scope. Suitable protecting groups and the methods for protecting anddeprotecting different substituents using such suitable protectinggroups are well known to those skilled in the art; examples of which maybe found in T. Greene and P. Wuts, Protecting Groups in ChemicalSynthesis (3^(rd) ed.), John Wiley & Sons, NY (1999), which isincorporated herein by reference in its entirety.

Furthermore, the skilled artisan will appreciate that in manycircumstances, the order in which moieties are introduced may not becritical. The particular order of steps required to produce thecompounds of formula (I) is dependent upon the particular compoundsbeing synthesized, the starting compound, and the relative lability ofthe substituted moieties. Thus, synthesis of the present compounds maybe accomplished by methods analogous to those described in the syntheticschemes described hereinabove and in specific examples, and routineexperimentations, including appropriate manipulation of the reactionconditions, reagents and sequence of the synthetic route are within thescope.

Starting materials, if not commercially available, may be prepared byprocedures selected from standard organic chemical techniques,techniques that are analogous to the synthesis of known, structurallysimilar compounds, or techniques that are analogous to the abovedescribed schemes or the procedures described in the synthetic examplessection.

When an optically active form of a compound is required, it may beobtained by carrying out one of the procedures described herein using anoptically active starting material (prepared, for example, by asymmetricinduction of a suitable reaction step), or by resolution of a mixture ofthe stereoisomers of the compound or intermediates using a standardprocedure (such as chromatographic separation, recrystallization orenzymatic resolution).

Similarly, when a pure geometric isomer of a compound is required, itmay be obtained by carrying out one of the above procedures using a puregeometric isomer as a starting material, or by resolution of a mixtureof the geometric isomers of the compound or intermediates using astandard procedure such as chromatographic separation.

Following Examples may be used for illustrative purposes and should notbe deemed to narrow the scope.

g. Examples Example 1N-[(2Z)-5-tert-butyl-3-{[1-(methylsulfonyl)azetidin-3-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-2-methoxy-5-(trifluoromethyl)benzamideExample 1A tert-butyl3-((5-tert-butyl-2-iminothiazol-3(2H)-yl)methyl)azetidine-1-carboxylate

A mixture of 3,3-dimethylbutanal (3.71 mL, 29.5 mmol), tert-butyl3-(aminomethyl)azetidine-1-carboxylate (Astatech, 5 g, 26.8 mmol), and 8g of 4 Å molecular sieves (8-12 mesh beads) in acetonitrile (50 mL) wasstirred at ambient temperature for 72 h. The material was filteredthrough Celite with acetonitrile (additional 25 mL) then potassiumthiocyanate (3.47 g, 35.7 mmol) was added and the mixture was warmed to50° C. Iodine (6.81 g, 26.8 mmol) was added and the mixture stirred at50° C. for 16 h then was cooled to ambient temperature. The mixture wasstirred with 75 mL of 20% aqueous sodium metabisulfite for 1 h then thelayers were separated and the aqueous layer was extracted with 3×10 mLCH₂Cl₂. The combined organics were dried over anhydrous Na₂SO₄,filtered, and concentrated under reduced pressure to give the crudetitle compound (6.3 g, 19.4 mmol, 72% yield) which was carried onwithout further purification. MS (DCI/NH₃) m/z 326 (M+H)⁺.

Example 1B 2-methoxy-5-(trifluoromethyl)benzoyl chloride

A solution of 2-methoxy-5-(trifluoromethyl)benzoic acid (0.68 g, 3.1mmol) in thionyl chloride (10 mL) was warmed to reflux and was allowedto stir for 2 h. The mixture was cooled to ambient temperature,concentrated under reduced pressure and diluted with 10 mL of toluene.This material was again concentrated under reduced pressure and wasagain diluted with 10 mL of toluene. This concentration and dilution wasrepeated for an additional time and the crude acid chloride was carriedon to the next step.

Example 1C (Z)-tert-butyl3-((5-tert-butyl-2-(2-methoxy-5-(trifluoromethyl)benzoylimino)thiazol-3(2H)-yl)methyl)azetidine-1-carboxylate

To a solution of the product of Example 1A (1 g, 3.1 mmol) intetrahydrofuran (20 mL) was added triethylamine (1.3 mL, 9.2 mmol).Example 1B (3 mmol) in 5 mL tetrahydrofuran was added via cannula. Thismixture was warmed to 50° C. and was allowed to stir for 4 h. Themixture was then stirred at ambient temperature for 72 h. The reactionmixture was quenched with 10 mL of saturated, aqueous NH₄Cl and thelayers were separated. The aqueous layer was extracted with 3×10 mLethyl acetate and the combined organics were dried over anhydrousNa₂SO₄, filtered, and concentrated under reduced pressure. The crudematerial was purified by column chromatography (SiO₂, 60% hexanes inethyl acetate) to give the title compound (0.55 g, 1.04 mmol, 34%yield). MS (DCI/NH₃) m/z 528 (M+H)⁺.

Example 1D(Z)—N-(3-(azetidin-3-ylmethyl)-5-tert-butylthiazol-2(3H)-ylidene)-2-methoxy-5-(trifluoromethyl)benzamide

To a solution of the product of Example IC (1.79 g, 3.4 mmol) in CH₂Cl₂(25 mL) at 0° C. was added trifluoroacetic acid (12 mL, 156 mmol)dropwise over 15 min. The mixture was allowed to warm to ambienttemperature and was allowed to stir for 3 hours. The mixture wasconcentrated under reduced pressure and purified by columnchromatography (SiO₂, 100% CH₂Cl₂ then 9:1:0.1 CH₂Cl₂:methanol:NH₄OH) togive the title compound (1.76 g, 3.29 mmol, 97% yield). MS (DCI/NH₃) m/z428 (M+H)⁺.

Example 1EN-[(2Z)-5-tert-butyl-3-{[1-(methylsulfonyl)azetidin-3-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-2-methoxy-5-(trifluoromethyl)benzamide

To a solution of the product of Example 1D (0.35 g, 0.66 mmol) andtriethyl amine (0.27 mL, 2.0 mmol) in tetrahydrofuran (10 mL) at 0° C.was added methanesulfonyl chloride (0.061 mL, 0.79 mmol). The mixturewas stirred at 0° C. for 10 min and then was allowed to warm to ambienttemperature and was stirred for 1 h. The reaction mixture was quenchedwith 5 mL saturated, aqueous NaHCO₃, the layers were separated and theaqueous layer was extracted with 3×5 mL ethyl acetate. The combinedorganics were dried over anhydrous Na₂SO₄, filtered, and concentratedunder reduced pressure. The crude material was purified by columnchromatography (SiO₂, 60% hexanes in ethyl acetate) to give the titlecompound (0.22 g, 0.44 mmol, 66% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm1.35 (s, 9 H), 2.83 (s, 3 H), 3.15-3.34 (m, 1 H), 3.84 (dd, J=8.1, 5.8Hz, 2 H), 3.97 (s, 3 H), 4.04 (t, J=8.3 Hz, 2 H), 4.42 (d, J=7.5 Hz,2H), 6.64 (s, 1H), 7.06 (d, J=8.7 Hz, 1 H), 7.65 (dd, J=8.7, 2.0 Hz, 1H), 8.22 (d, J=2.4 Hz, 1 H); MS (DCI/NH₃) m/z 506 (M+H)⁺; Anal.calculated for C₂₁H₂₆F₃N₃O₄S₂: C, 49.89; H, 5.18; N, 8.31. Found: C,49.93; H, 5.16; N, 8.05.

Example 2N-[(2Z)-5-tert-butyl-3-{[1-(cyclopropylsulfonyl)azetidin-3-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-2-methoxy-5-(trifluoromethyl)benzamide

To a solution of the product of Example 1D (0.35 g, 0.66 mmol) andtriethyl amine (0.27 mL, 2.0 mmol) in tetrahydrofuran (10 mL) at 0° C.was added cyclopropanesulfonyl chloride (0.080 mL, 0.79 mmol). Themixture was stirred at 0° C. for 10 minutes and then was allowed to warmto ambient temperature and was stirred for 2 h. The mixture was quenchedwith 5 mL saturated, aqueous NaHCO₃, the layers were separated and theaqueous layer was extracted with 3×5 mL ethyl acetate. The combinedorganics were dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The crude material was purified by columnchromatography (SiO₂, 60% hexanes in ethyl acetate) to give the titlecompound (0.25 g, 0.47 mmol, 72% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm0.90-1.00 (m, 2 H), 1.06-1.17 (m, 2 H), 1.35 (s, 9 H), 2.22-2.36 (m, 1H), 3.17-3.33 (m, 1 H), 3.85 (dd, J=8.1, 5.8 Hz, 2 H), 3.97 (s, 3 H),4.06 (t, J=8.1 Hz, 2 H), 4.42 (d, J=7.1 Hz, 2 H), 6.64 (s, 1 H), 7.05(d, J=8.8 Hz, 1 H), 7.64 (dd, J=9.0, 2.9 Hz, 1H), 8.21 (d, J=2.4 Hz, 1H)); MS (DCI/NH₃) m/z 532 (M+H)⁺; Anal. calculated forC₂₃H₂₈F₃N₃O₄S₂.0.1C₄H₈O₂: C, 52.01; H, 5.37; N, 7.78. Found: C, 52.01;H, 4.98; N, 7.43.

Example 35-chloro-2-methoxy-N-[(2Z)-5-methyl-3-{[1-(methylsulfonyl)azetidin-3-yl]methyl}-1,3-thiazol-2(3H)-ylidene]benzamideExample 3A tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate

To a solution of 1-Boc-azetidine-3-carboxylic acid (Astatech, 1.0 g,4.97 mmol) in tetrahydrofuran (10 mL) at −10° C. was added4-methylmorpholine (0.55 mL, 5.0 mmol). This mixture was stirred for 1minute and then ethyl chloroformate (0.47 mL, 4.97 mmol) was addeddropwise. The mixture was stirred at −10° C. for 15 min then wasfiltered through Celite and the filtrate was added dropwise via syringeto a mixture of NaBH₄ (0.42 g, 11.2 mmol) in H₂O (5 mL) at 5° C. Themixture was allowed to warm to ambient temperature and was stirredvigorously for 3 h. The reaction mixture was quenched with 5 mLsaturated, aqueous NH₄Cl, the layers were separated and the aqueouslayer was extracted with 3×5 mL ethyl acetate. The combined organicswere dried over anhydrous Na₂SO₄, filtered, concentrated under reducedpressure and purified by column chromatography (SiO₂, 30% hexanes inethyl acetate) to give the title compound (0.62 g, 3.3 mmol, 66% yield).MS (DCI/NH₃) m/z 188 (M+H)⁺.

Example 3B tert-butyl 3-(tosyloxymethyl)azetidine-1-carboxylate

To a solution of the product of Example 3A (0.62 g, 3.3 mmol) in CH₂Cl₂(7 mL) and pyridine (7 mL) was added p-toluenesulfonyl chloride (0.63 g,3.3 mmol) portionwise over 5 min. The mixture was stirred at ambienttemperature for 24 h then was quenched with 10 mL 5% aqueous HCl. Thelayers were separated and the aqueous layer was extracted (3×5 mLCH₂Cl₂). The combined organics were dried over anhydrous Na₂SO₄,filtered, concentrated under reduced pressure and purified by columnchromatography (SiO₂, 50% hexanes in ethyl acetate) to give the titlecompound (0.95 g, 2.8 mmol, 84% yield). MS (DCI/NH₃) m/z 359 (M+NH₄)⁺.

Example 3C tert-butyl3-((2-imino-5-methylthiazol-3(2H)-yl)methyl)azetidine-1-carboxylate

A mixture of 2-amino-5-methylthiazole (0.32 g, 2.8 mmol), the product ofExample 3B (0.95 g, 2.8 mmol) and tetrabutylammonium iodide (0.51 g, 1.4mmol) in 1 mL N,N-dimethylformamide was warmed to 85° C. and was allowedto stir for 16 h. The mixture was allowed to cool to ambienttemperature, was diluted with CH₂Cl₂ (10 mL) and washed with 5 mLsaturated, aqueous NaHCO₃. The layers were separated and the aqueouslayer was extracted with 3×5 mL CH₂Cl₂. The combined organics were driedover anhydrous Na₂SO₄, filtered, concentrated under reduced pressure andpurified by column chromatography (SiO₂, 10% CH₃OH in ethyl acetate then9:1:0.1 CH₂Cl₂:CH₃OH:NH₄OH) to give the title compound (0.55 g, 1.9mmol, 69% yield). MS (DCI/NH₃) m/z 284 (M+NH₄)⁺.

Example 3D 5-chloro-2-methoxybenzoyl chloride

A solution of 5-chloro-2-methoxybenzoic acid (0.37 g, 2.0 mmol) in 10 mLof SOCl₂ was warmed to reflux and was allowed to stir for 2 hours. Themixture was cooled to ambient temperature and concentrated under reducedpressure. The crude material was diluted with 5 mL of toluene andconcentrated under reduced pressure. This dilution with toluene andconcentration was repeated two additional times to afford the titlecompound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 3.82 (s, 3 H),7.16 (d, J=8.8 Hz, 1 H), 7.49-7.59 (m, 1 H), 7.61 (d, J=2.7 Hz, 1 H).

Example 3E (Z)-tert-butyl3-((2-(5-chloro-2-methoxybenzoylimino)-5-methylthiazol-3(2H)-yl)methyl)azetidine-1-carboxylate

To a solution of the product of Example 3C (0.55 g, 1.9 mmol) intetrahydrofuran (15 mL) was added triethyl amine (0.81 mL, 5.8 mmol)followed by Example 3D (1.9 mmol) in 3 mL tetrahydrofuran. This mixturewas warmed to 50° C. and was stirred for 4 h. The mixture was cooled toambient temperature, was quenched with 10 mL NH₄Cl and the resultinglayers were separated. The aqueous layer was extracted with 3×5 mL ethylacetate and the combined organics were dried over anhydrous Na₂SO₄,filtered, concentrated under reduced pressure and purified by columnchromatography (SiO₂, 40% hexanes in ethyl acetate) to give the titlecompound (0.56 g, 1.2 mmol, 64% yield). MS (DCI/NH₃) m/z 452 (M+NH₄)⁺.

Example 3F(Z)—N-(3-(azetidin-3-ylmethyl)-5-methylthiazol-2(3H)-ylidene)-5-chloro-2-methoxybenzamide

To a solution of the product of Example 3E (0.52 g, 1.15 mmol) in CH₂Cl₂(10 mL) at 0° C. was added trifluoroacetic acid (5 mL) dropwise viasyringe. The mixture was allowed to warm to ambient temperature and wasstirred for 2 h. The mixture was concentrated under reduced pressure andpurified by column chromatography (SiO₂, 9:1:0.1 CH₂Cl₂:CH₃OH:NH₄OH) togive the title compound (0.36 g, 1.0 mmol, 89% yield). MS (DCI/NH₃) m/z352 (M+NH₄)⁺.

Example 3G5-chloro-2-methoxy-N-[(2Z)-5-methyl-3-{[1-(methylsulfonyl)azetidin-3-yl]methyl}-1,3-thiazol-2(3H)-ylidene]benzamide

To a solution of the product of Example 3F (0.15 g, 0.43 mmol) intetrahydrofuran (10 mL) at ambient temperature was added triethyl amine(0.18 mL, 1.3 mmol) followed by methanesulfonyl chloride (40 μL, 0.51mmol). This mixture was stirred at ambient temperature for 24 h then wasquenched with 5 mL saturated, aqueous NaHCO₃. The layers were separatedand the aqueous layer was extracted 3×5 mL ethyl acetate. The combinedorganics were dried over anhydrous Na₂SO₄, filtered, concentrated underreduced pressure and purified by column chromatography (SiO₂, 20%hexanes in ethyl acetate) to give the title compound (0.13 g, 0.30 mmol,70% yield). ¹H NMR (300 MHz, CD₃OD) δ ppm 2.34 (d, J=1.4 Hz, 3 H), 2.89(s, 3 H), 3.11-3.26 (m, 1 H), 3.87 (dd, J=8.3, 5.9 Hz, 2 H), 3.86 (s, 3H), 4.00 (t, J=8.3 Hz, 2 H), 4.50 (d, J=7.1 Hz, 2 H), 7.08 (d, J=8.8 Hz,1 H), 7.15-7.20 (m, 1 H), 7.40 (dd, J=8.8, 2.7 Hz, 1 H), 7.80 (d, J=2.7Hz, 1 H); MS (DCI/NH₃) m/z 430 (M+H)⁺; Anal. calculated forC₁₇H₂₀ClN₃O₄S₂: C, 47.49; H, 4.69; N, 9.77. Found: C, 47.64; H, 4.65; N,9.46.

Example 4N-[(2Z)-5-tert-butyl-3-{[(2R)-5-oxopyrrolidin-2-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 4A (R)-(5-oxopyrrolidin-2-yl)methyl 4-methylbenzenesulfonate

To a mixture of (R)-ethyl 5-oxopyrrolidin-2-carboxylate (Aldrich, 3 g,19 mmol) and sodium borohydride (1.89 g, 50 mmol) in tetrahydrofuran (30mL) at 50° C. was added dropwise for 30 min methanol (10 mL). Thereaction was then continued for an additional 15 min and cooled to roomtemperature. The mixture was treated with 1N HCl to pH=3 andconcentrated under reduced pressure. The residue was triturated withanhydrous methanol and the solid was filtered off and washed withmethanol. The filtrate and washings were combined and concentrated underreduced pressure. The concentrate was then triturated with anhydroustetrahydrofuran and filtered. The filtrate was concentrated underreduced pressure and the concentrate was dissolved in anhydrous CH₂Cl₂(20 mL). p-Toluenesulfonyl chloride (3.64 g, 19 mmol) was added, themixture was cooled to 0° C. and triethylamine (2.66 mL, 19 mmol) wasadded dropwise. The reaction mixture was allowed to warm to roomtemperature and stirred for 12 h. The mixture was then washed withwater, brine, dried with anhydrous MgSO₄ and concentrated under reducedpressure. The residue was chromatographed (SiO₂, ethyl acetate-ethanol9:1) to afford 3.5 g of the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ1.62 (m 1H), 2.06 (m, 3H), 2.42 (s, 3H), 3.71 (m, 1H), 3.87 (dd, J=10Hz, 4 Hz, 1H), 3.97 (dd, J=10 Hz, 4 Hz, 1H), 7.49 (d, J=9 Hz, 2H), 7.75(broad s, 1H), 7.82 (d, J=9 Hz, 2H); MS (DCI/NH₃) m/z 270 (M+H)⁺, 287(M+NH₄)⁺.

Example 4B 5-tert-butylthiazol-2-amine

To a solution of 3,3-dimethylbutyraldehyde (10 g, 99.8 mmol) in 200 mLof cyclohexane was added pyrrolidine (8.7 mL, 0.11 mol) followed byp-toluenesulfonic acid monohydrate (0.95 g, 5.0 mmol). This reactionflask was equipped with a Dean-Stark trap and the mixture was warmed toreflux and was allowed to stir for 3 hours. The mixture was cooled toambient temperature, filtered, and concentrated under reduced pressure.The residue was dissolved in 75 mL of CH₃OH, sulfur was added (3.2 g,99.8 mmol), and the mixture was cooled to 0° C. Cyanamide (4.2 g, 99.8mmol) was added portion-wise over 10 minutes and the mixture was allowedto warm to ambient temperature and stir for 18 hours. The reactionmixture was concentrated under reduced pressure and purified by columnchromatography (SiO₂, ethyl acetate then 10% methanol in ethyl acetate)to afford the title compound. MS (DCI/NH₃) m/z 157 (M+H)⁺.

Example 4C N-(5-tert-butylthiazol-2-yl)-5-chloro-2-methoxybenzamide

To a solution of Example 4B (0.94 g, 6.0 mmol) in tetrahydrofuran (40mL) was added Example 3D (1.23 g, 6.0 mmol), triethylamine (2.4 mL, 18mmol), and 4-dimethylaminopyridine (7.5 mg, 0.06 mmol). The reactionmixture was stirred at 60° C. for 14 hours and then cooled to ambienttemperature, diluted with saturated aqueous NaHCO₃ (20 mL) and extractedwith ethyl acetate (3×30 mL). The combined organic extracts were driedover anhydrous Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by column chromatography using anAnalogix® Intelliflash280 ™ (SiO₂, 0-100% ethyl acetate in hexanes) toafford the title compound. MS (ESI⁺) m/z 325 (M+H)⁺.

Example 4DN-[(2Z)-5-tert-butyl-3-{[(2R)-5-oxopyrrolidin-2-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

A mixture of Example 4C (650 mg, 2 mmol), Example 4A (700 mg, 2.6 mmol),potassium carbonate (653 mg, 4 mmol), tetrabutylammonium iodide (20 mg,0.05 mmol), tetrabutylammonium hydrogensulfate (20 mg, 0.06 mmol) andtetraethylammonium iodide (20 mg, 0.07 mmol) in anhydrous toluene (60mL) was refluxed for 15 h. The mixture was then washed with water,brine, dried with anhydrous MgSO₄, filtered, and concentrated underreduced pressure. The residue was chromatographed (SiO₂, ethylacetate-ethanol 9:1) to afford 490 mg of the title compound. ¹H NMR (300MHz, DMSO-d₆) δ 1.31 (s, 9H), 1.83 (m, 1H), 2.07 (m, 3H), 3.78 (s, 3H),4.09 (m, 2H), 4.30 (m, 1H), 7.10 (d, J=9 Hz, 1H), 7.27 (s, 1H), 7.45(dd, J=9 Hz, 3 Hz, 1H), 7.62 (d, J=3 Hz, 1H), 7.85 (broad s, 1H); MS(DCI/NH₃) m/z 422 (M+H)⁺.

Example 5N-[(2Z)-5-tert-butyl-3-{[(2S)-5-oxopyrrolidin-2-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

A mixture of Example 4C (810 mg, 2.49 mmol),(S)-(5-oxopyrrolidin-2-yl)methyl 4-methylbenzenesulfonate (Aldrich, 807mg, 3 mmol), potassium carbonate (828 mg, 6 mmol), tetrabutylammoniumiodide (20 mg, 0.05 mmol), tetrabutylammonium hydrogensulfate (20 mg,0.06 mmol) and tetraethylammonium iodide (20 mg, 0.07 mmol) in anhydroustoluene (100 mL) was refluxed for 15 h. The mixture was cooled to roomtemperature, washed with water, brine, dried with anhydrous MgSO₄,filtered, and concentrated under reduced pressure. The residue waschromatographed (SiO₂, ethyl acetate-ethanol 9:1) to afford 510 mg ofthe title compound. ¹H NMR (300 MHz, DMSO-d₆) δ 1.32 (s, 9H), 1.83 (m,1H), 2.07 (m, 3H), 3.78 (s, 3H), 4.09 (m, 2H), 4.30 (m, 1H), 7.10 (d,J=9 Hz, 1H), 7.27 (s, 1H), 7.45 (dd, J=9 Hz, 3 Hz, 1H), 7.62 (d, J=3 Hz,1H), 7.82 (broad s, 1H); MS (DCI/NH₃) m/z 422 (M+H)⁺. Anal. calcd forC₂₀H₂₄ClN₃O₃S.0.25H₂O: C, 56.33; H, 5.79; N, 9.85. Found: C, 56.42; H,5.55; N, 9.25.

Example 6N-[(2Z)-5-tert-butyl-3-{[(2S)-5-oxopyrrolidin-2-yl]methyl}-1,3,4-thiadiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 6AN-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-5-chloro-2-methoxybenzamide

To a solution of 5-tert-butyl-1,3,4-thiadiazole-2-amine (Aldrich, 1.57g, 10 mmol) and Example 3D (2.05 g, 10 mmol) in anhydrous CH₂Cl₂ (45 mL)at 0° C. was added dropwise triethylamine (1.67 mL, 12 mmol) and thereaction mixture was allowed to warm to room temperature and stirred for12 h. The mixture was then washed with water, brine, dried withanhydrous MgSO₄, filtered, and concentrated under reduced pressure toafford 3.2 g of the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ 1.42 (s,9H), 3.87 (s, 3H), 7.22 (d, J=9 Hz, 1H), 7.60 (m, 2H), 12.40 (broad s,1H); MS (DCI/NH₃) m/z 326 (M+H)⁺.

Example 6BN-[(2Z)-5-tert-butyl-3-{[(2S)-5-oxopyrrolidin-2-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

A mixture of Example 6A (325 mg, 1 mmol),(S)-(5-oxopyrrolidin-2-yl)methyl 4-methylbenzenesulfonate (Aldrich, 400mg, 1.5 mmol), potassium carbonate (276 mg, 2 mmol), tetrabutylammoniumiodide (15 mg, 0.04 mmol), tetrabutylammonium hydrogensulfate (15 mg,0.04 mmol) and tetraethylammonium iodide (15 mg, 0.06 mmol) in anhydroustoluene (50 mL) was refluxed for 15 h. The mixture was then cooled toroom temperature, washed with water, brine, dried with anhydrous MgSO₄,filtered, and concentrated under reduced pressure. The residue waspurified by chromatography (SiO₂, ethyl acetate-ethanol 9:1) to afford260 mg of the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ 1.38 (s, 9H),1.90 (m, 1H), 2.12 (m, 3H), 3.80 (s, 3H), 4.10 (m, 1H), 4.27 (dd, J=13Hz, 6 Hz, 1H), 4.44 (dd, J=13 Hz, 6 Hz), 7.14 (d, J=9 Hz, 1H), 7.50 (dd,J=9 Hz, 3 Hz, 1H), 7.71 (d, J=3 Hz, 1H), 7.80 (broad s, 1H); MS(DCI/NH₃) m/z 423 (M+H)⁺. Anal. calcd for C₁₉H₂₃ClN₄O₃S.0.25H₂O: C,53.39; H, 5.54; N, 13.11. Found: C, 53.59; H, 5.41; N, 12.79.

Example 7N-[(2Z)-5-tert-butyl-3-{[(2R)-5-oxopyrrolidin-2-yl]methyl}-1,3,4-thiadiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

A mixture of Example 6A (650 mg, 2 mmol), Example 4A (807 mg, 3 mmol),potassium carbonate (522 mg, 3.8. mmol), tetrabutylammonium iodide (20mg, 0.05 mmol), tetrabutylammonium hydrogensulfate (20 mg, 0.06 mmol)and tetraethylammonium iodide (15 mg, 0.06 mmol) in anhydrous toluene(80 mL) was refluxed for 15 h. The mixture was then cooled to roomtemperature, washed with water, brine, dried with anhydrous MgSO₄,filtered, and concentrated under reduced pressure. The residue waspurified by chromatography (SiO₂, ethyl acetate-ethanol 9:1) to afford540 mg of the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ 1.38 (s, 9H),1.90 (m, 1H), 2.12 (m, 3H), 3.80 (s, 3H), 4.10 (m, 1H), 4.27 (dd, J=13Hz, 6 Hz, 1H), 4.44 (dd, J=13 Hz, 6 Hz), 7.14 (d, J=9 Hz, 1H), 7.50 (dd,J=9 Hz, 3 Hz, 1H), 7.71 (d, J=3 Hz, 1H), 7.85 (broad s, 1H); MS(DCI/NH₃) m/z 423 (M+H)⁺. Anal. calcd for C₁₉H₂₃ClN₄O₃S: C, 53.96; H,5.48; N, 13.25. Found: C, 54.35; H, 5.60; N, 12.88.

Example 8N-[(2Z)-5-tert-butyl-3-{[(2S)-1-methyl-5-oxopyrrolidin-2-yl]methyl}-1,3,4-thiadiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 8A (5S)-5-(hydroxymethyl)-1-methylpyrrolidin-2-one

To a solution of (S)-methyl 5-oxo-pyrrolidine-2-carboxylate (Aldrich,2.86 g, 20 mmol) in tetrahydrofuran (50 mL) at 0° C. was added inportions 60% oil dispersion NaH (720 mg, 30 mmol). Methyl iodide (1.88mL, 30 mmol) was added and the mixture was allowed to warm to ambienttemperature and stirred for 16 h. The mixture was concentrated underreduced pressure and residue was partitioned between water and ethylacetate. The organic layer was washed with water, brine, dried withanhydrous MgSO₄, filtered, and concentrated under reduced pressure. Theresidue was redissolved in anhydrous tetrahydrofuran (50 mL), sodiumborohydride (946 mg, 25 mmol) was added followed by dropwise addition(˜20 min) of methanol (20 mL) at 50° C. The reaction mixture was stirredfor an additional 1 h at a range from 45° C. to 50° C., then cooled toroom temperature and concentrated under reduced pressure. Citric acid(10%) was added and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water, brine, dried with anhydrous MgSO₄,filtered, and concentrated under reduced pressure. The residue waspurified by chromatography (SiO₂, ethyl acetate-ethanol 4:1) to afford1.3 g of the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ 1.77 (m 1H),1.95 (m, 1H), 2.18 (m, 2H), 2.69 (s, 3H), 3.43 (m, 2H), 3.55 (m, 1H),4.77 (t, J=6 Hz, 1H); MS (DCI/NH₃) m/z 130 (M+H)⁺, 147 (M+NH₄)⁺.

Example 8B [(2S)-1-methyl-5-oxopyrrolidin-2-yl]methyl4-methylbenzenesulfonate

Example 8A (1.29 g, 10 mmol) was dissolved in anhydrous CH₂Cl₂ (60 mL),p-toluenesulfonyl chloride (2.1 g (11 mmol) was added followed bydropwise addition of triethylamine at 0° C. The reaction mixture wasallowed to warm to ambient temperature and stirred for 16 h, washed withwater, brine, dried with anhydrous MgSO₄, filtered, and concentratedunder reduced pressure. The residue was purified by chromatography(SiO₂, ethyl acetate-ethanol 9:1) to afford 1.5 g of the title compound.¹H NMR (300 MHz, DMSO-d₆) δ 1.62 (m 1H), 2.06 (m, 3H), 2.42 (s, 3H),2.57 (s, 3H), 3.72 (sextet, J=4 Hz, 1H), 4.06 (dd, J=10 Hz, 4 Hz, 1H),4.22 (dd, J=10 Hz, 4 Hz, 1H), 7.50 (d, J=9 Hz, 2H), 7.80 (d, J=9 Hz,2H); MS (DCI/NH₃) m/z 284 (M+H)⁺, 301 (M+NH₄)⁺.

Example 8CN-[(2Z)-5-tert-butyl-3-{[(2S)-1-methyl-5-oxopyrrolidin-2-yl]methyl}-1,3,4-thiadiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

A mixture of Example 6A (325 mg, 1 mmol), Example 8B (300 mg, 1.1 mmol),potassium carbonate (300 mg, 2.2. mmol), tetrabutylammonium iodide (15mg (0.04 mmol), tetrabutylammonium hydrogensulfate (15 mg, 0.04 mmol)and tetraethylammonium iodide (15 mg, 0.05 mmol) in anhydrous toluene(50 mL) was refluxed for 15 h. The mixture was then cooled to roomtemperature, washed with water, brine, dried with anhydrous MgSO₄,filtered, and concentrated under reduced pressure. The residue waspurified by chromatography (SiO₂, ethyl acetate) to afford 317 mg of thedesired product. ¹H NMR (300 MHz, DMSO-d₆) δ 1.36 (s, 9H), 1.75 (m, 1H),2.00 (m, 3H), 2.77 (s, 3H), 3.80 (s, 3H), 4.05 (m, 1H), 4.46 (dd, J=13Hz, 6 Hz, 1H), 4.65 (dd, J=13 Hz, 6 Hz), 7.15 (d, J=9 Hz, 1H), 7.50 (dd,J=9 Hz, 3 Hz, 1H), 7.77 (d, J=3 Hz, 1H); MS (DCI/NH₃) m/z 437 (M+H)⁺.Anal. calcd for C₂₀H₂₅ClN₄O₃S: C, 54.97; H, 5.77; N, 12.82. Found: C,54.90; H, 5.80; N, 12.63.

Example 9N-[(2Z)-5-tert-butyl-3-{[1-(methylsulfonyl)azetidin-3-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 9A tert-butyl3-((5-tert-butyl-2-iminothiazol-3(2H)-yl)methyl)azetidine-1-carboxylate

3,3-Dimethylbutanal (0.7 mL, 5.4 mmol), tert-butyl3-(aminomethyl)azetidine-1-carboxylate (Astatech, 1.0 g, 5.4 mmol) weremixed with 2 g of 4 Å molecular sieves in 5 mL of dry acetonitrile atroom temperature for 20 hours. The reaction was filtered through Celite,washed with 5 mL of acetonitrile and the filtrate used without furtherpurification. Potassium thiocyanate (0.7 g, 7.1 mmol) was added and themixture heated to 50° C. for 10 minutes. Iodine (1.4 g, 5.4 mmol) wasadded and the reaction mixture was continued to stir at 50° C. for 6hours. The reaction mixture was cooled to room temperature, 10 mL ofacetonitrile was added, followed by 10 mL of 20% Na₂S₂O₅. The phaseswere separated and the organic phase was dried with Na₂SO₄, filtered,and the solvent removed to provide the title compound. LC/MS m/z 326.3(M+H)⁺. The product was used without further purification.

Example 9B (Z)-tert-butyl3-((5-tert-butyl-2-(5-chloro-2-methoxybenzoylimino)thiazol-3(2H)-yl)methyl)azetidine-1-carboxylate

5-Chloro-2-methoxybenzoic acid (1.0 g, 5.4 mmol) was dissolved in 3 mLof CH₂Cl₂ and 8 mL of oxalyl chloride (2M in CH₂Cl₂) was added followedby 20 μL of N,N-dimethylformamide. The reaction mixture was stirred atroom temperature for 1 hour. The solvent was removed and the residuetreated with toluene and solvent removed under vacuum. The residue wassuspended in 6 mL of tetrahydrofuran, Example 9A (1.7 g, 5.4 mmol) wasadded, followed by triethylamine (2.2 mL, 16.1 mmol). The reactionmixture was stirred at room temperature for 2 hours then diluted withethyl acetate (100 mL). The organic phase was washed with water, brine,dried with MgSO₄, filtered, and concentrated. The concentrate waspurified by flash chromatography on SiO₂ eluting with a gradient from 0to 50% ethyl acetate in hexanes over 1000 mL then isocratic for 1000 mLto provide the title compound (1.1 g, 2.2 mmol, 41%). MS (DCI/NH₃) m/z494.2 (M+H)⁺. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.34 (s, 9 H) 1.44 (s, 9 H)3.10-3.26 (m, 1 H) 3.77 (dd, J=8.82, 5.43 Hz, 2 H) 3.90 (s, 3 H) 4.05(t, J=8.48 Hz, 2 H) 4.36 (s, 2 H) 6.62 (s, 1 H) 6.90 (d, J=8.82 Hz, 1 H)7.33 (dd, J=8.82, 2.71 Hz, 1 H) 7.89 (d, J=3.05 Hz, 1 H).

Example 9C(Z)—N-(3-(azetidin-3-ylmethyl)-5-tert-butylthiazol-2(3H)-ylidene)-5-chloro-2-methoxybenzamide

Example 9B (1.1 g, 2.2 mmol) was dissolved in 8 mL of CH₂Cl₂, 2 mL oftrifluoroacetic acid was added, and the reaction mixture was stirred atroom temperature for 4 hours. The solvent was removed and theconcentrate purified by flash chromatography on SiO₂ using a gradientfrom 0% methanol/CH₂Cl₂ to 10% methanol/CH₂Cl₂ (0.1% NH₄OH) over 300 mLthen isocratic for 240 mL to provide the title compound (0.7 g, 1.9mmol, 82% yield). MS (DCI/NH₃) m/z 394.1 (M+H)⁺. ¹H NMR (300 MHz, CDCl₃)δ ppm 1.33 (s, 9 H) 3.52-3.66 (m, 1 H) 3.87 (s, 3 H) 3.92-4.02 (m, 2 H)4.14 (t, J=9.32 Hz, 2 H) 4.47 (d, J=7.12 Hz, 2 H) 6.78 (s, 1 H) 6.89 (d,J=8.82 Hz, 1 H) 7.32 (dd, J=8.82, 2.71 Hz, 1 H) 7.82 (d, J=2.71 Hz, 1 H)9.84 (s, 1 H).

Example 9DN-[(2Z)-5-tert-butyl-3-{[1-(methylsulfonyl)azetidin-3-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

Example 9C (0.6 g, 1.5 mmol) was dissolved in 15 mL of tetrahydrofuran,triethylamine (0.64 mL, 4.6 mmol) was added followed by methanesulfonylchloride (0.14 mL, 1.8 mmol). The reaction mixture was stirred at roomtemperature for 1 hour, and diluted with ethyl acetate (100 mL). Theorganic phase was washed with water, brine, dried with MgSO₄, filtered,and concentrated. The concentrate was purified by flash chromatographyon SiO₂, eluting with a gradient from CH₂Cl₂ to 10% B/CH₂Cl₂ (B=10%methanol/CH₂Cl₂ 0.1% NH₄OH) over 450 mL then isocratic for 300 mL toprovide the title compound (0.36 g, 0.76 mmol, 50% yield). MS (DCI/NH₃)m/z 472.1 (M+H)⁺. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.35 (s, 9 H) 2.85 (s, 3H) 3.17-3.31 (m, 1 H) 3.84 (dd, J=8.31, 5.59 Hz, 2 H) 3.90 (s, 3 H) 4.04(t, J=8.31 Hz, 2 H) 4.42 (d, J=7.46 Hz, 2 H) 6.63 (s, 1 H) 6.92 (d,J=8.82 Hz, 1 H) 7.34 (dd, J=8.82, 2.71 Hz, 1 H) 7.91 (d, J=2.71 Hz, 1H).

Example 10N-[(2Z)-5-tert-butyl-3-{2-[methyl(methylsulfonyl)amino]ethyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 10A tert-butyl2-(5-tert-butyl-2-iminothiazol-3(2H)-yl)ethylcarbamate

tert-Butyl 2-aminoethylcarbamate (5.9 g, 37 mmol) and3,3-dimethylbutanal (4.9 mL 95%, 37 mmol) were mixed in dry acetonitrile(30 mL) with 4 g of 4 Å (8-12 mesh beads) molecular sieves and stirredat room temperature for 24 hours. The reaction mixture was filteredthrough Celite and washed with acetonitrile (5 mL). Potassiumthiocyanate (4.8 g, 49 mmol) was added and the mixture warmed to 50° C.for 10 minutes. Iodine (9.3 g, 37 mmol) was added and the reactionmixture was stirred at 50° C. for 6 hours. Acetonitrile (30 mL) wasadded followed by 10 mL of 20% Na₂S₂O₅. The layers were separated andthe organic layer was dried with Na₂SO₄, filtered, and concentrated. Theconcentrate was purified by flash chromatography on SiO₂, equilibratingthe column with CH₂Cl₂, loading the sample, and eluting with 5% methanolin CH₂Cl₂ (0.1% NH₄OH) isocratically to provide the title compound (3.5g, 11.7 mmol, 32% yield). MS (DCI/NH₃) m/z 300.2 (M+H)⁺. ¹H NMR (300MHz, CDCl₃) δ ppm 1.31 (s, 9 H) 1.42 (s, 9 H) 3.57 (q, J=6.78 Hz, 2 H)4.26 (t, J=6.95 Hz, 2 H) 5.63 (t, J=5.76 Hz, 1 H) 6.58 (s, 1 H).

Example 10B (Z)-tert-butyl2-(5-tert-butyl-2-(5-chloro-2-methoxybenzoylimino)thiazol-3(2H)-yl)ethylcarbamate

5-Chloro-2-methoxybenzoic acid (0.8 g, 4.3 mmol) was dissolved in 8 mLof CH₂Cl₂, oxalyl chloride (2M in CH₂Cl₂, 6.5 mL, 13 mmol) andN,N-dimethylformamide (20 μL) were added. The reaction mixture wasstirred at room temperature for 1 hour. The solvent was removed and theresidue dried twice from toluene. The residue was suspended in 5 mL oftetrahydrofuran, treated with Example 10A (1.3 g, 4.3 mmol) thentriethylamine (1.8 mL, 12.9 mmol) and the reaction mixture was stirredat room temperature for 1 hour, diluted with ethyl acetate (100 mL), andseparated. The organic phase was washed with water, brine, dried withMgSO₄, filtered, and concentrated. The residue was purified by flashchromatography on SiO₂, eluting with a gradient from 0 to 75% ethylacetate in hexane over 750 mL then isocratic for 600 mL to provide thetitle compound (1.7 g, 3.6 mmol, 85% yield). MS (DCI/NH₃) m/z 468.2(M+H)⁺. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.35 (s, 9 H) 1.39 (s, 9 H) 3.57(q, J=5.82 Hz, 2 H) 3.90 (s, 3 H) 4.33 (t, J=5.75 Hz, 2 H) 5.41 (s, 1 H)6.64 (s, 1 H) 6.91 (d, J=9.12 Hz, 1 H) 7.34 (dd, J=8.72, 2.78 Hz, 1 H)7.93 (d, J=2.78 Hz, 1 H).

Example 10C (Z)-tert-butyl2-(5-tert-butyl-2-(5-chloro-2-methoxybenzoylimino)thiazol-3(2H)-yl)ethyl(methyl)carbamate

Example 10B (0.5 g, 1.1 mmol) was dissolved in 4 mL ofN,N-dimethylformamide and cooled to 0° C., treated with iodomethane(0.33 mL, 2.2 mmol) followed by NaH (60%, 0.056 g, 1.4 mmol). Thereaction mixture was allowed to warm to ambient temperature and stirredfor 1 hour. Ethyl acetate (100 mL) was added and the organic phase waswashed with 20% NH₄Cl, water, brine, dried with MgSO₄, filtered, andconcentrated to provide the title compound (0.45 g, 0.9 mmol, 87%yield). LCMS m/z 482.2 (M+H)⁺.

Example 10D(Z)—N-(5-tert-butyl-3-(2-(methylamino)ethyl)thiazol-2(3H)-ylidene)-5-chloro-2-methoxybenzamide

Example 10C (0.45 g, 0.9 mmol) was dissolved in 10 mL of CH₂Cl₂, treatedwith 2 mL of trifluoroacetic acid, and was stirred at room temperaturefor 90 minutes. The solvent was removed and the residue was treated withCH₂Cl₂ and concentrated. The residue was dissolved in 5% methanol/CH₂Cl₂(0.1% NH₄OH), filtered through silica and washed with 5% methanol/CH₂Cl₂(0.1% NH₄OH). The filtrate was concentrated to provide the titlecompound. LCMS m/z 382.2 (M+H)⁺.

Example 10EN-[(2Z)-5-tert-butyl-3-{2-[methyl(methylsulfonyl)amino]ethyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

Example 10D (0.36 g, 0.9 mmol) was dissolved in 13 mL oftetrahydrofuran, treated with methanesulfonyl chloride (0.073 mL, 0.9mmol) and triethylamine (0.39 mL, 0.29 mmol), and stirred at roomtemperature for 1 hour. The mixture was diluted with ethyl acetatewashed with water, brine, dried with MgSO₄, filtered, and concentrated.The residue was purified by flash chromatography (SiO₂, 0 to 75% ethylacetate in hexane over 750 mL then isocratic for 300 mL) to provide thetitle compound (0.3 g, 0.65 mMol, 69% yield). MS (DCI/NH₃) m/z 460.1(M+H)⁺. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.35 (s, 9 H) 2.79 (s, 3 H) 2.83(s, 3 H) 3.61 (t, J=6.44 Hz, 2 H) 3.91 (s, 3 H) 4.38 (t, J=6.27 Hz, 2 H)6.74 (s, 1 H) 6.92 (d, J=8.82 Hz, 1 H) 7.34 (dd, J=8.99, 2.88 Hz, 1 H)8.00 (d, J=2.71 Hz, 1 H).

Example 11N-[(2Z)-5-tert-butyl-3-[2-(dimethylamino)ethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

Example 10B (0.35 g, 0.75 mmol) was mixed with 5 mL of 37% aqformaldehyde and mL of 88% formic acid. The mixture was refluxed at 100°C. for 3 hours. Reaction mixture was cooled, concentrated, diluted withethyl acetate (100 mL), washed with 2N NaOH, water, brine, dried withMgSO₄, filtered, and concentrated. The concentrate was purified by flashchromatography (SiO₂, eluting with a gradient from 0 to 15% methanol inCH₂Cl₂ (0.1% NH4OH) over 240 mL then isocratic for 300 mL) to providethe title compound (0.15 g, 0.38 mmol, 50% yield). MS (DCI/NH₃) m/z396.2 (M+H)⁺. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.35 (s, 9 H) 2.63 (s, 6 H)3.16-3.24 (m, 2 H) 3.91 (s, 3 H) 4.50-4.59 (m, 2 H) 6.88 (s, 1 H) 6.92(d, J=8.73 Hz, 1 H) 7.35 (dd, J=8.73, 2.78 Hz, 1 H) 7.98 (d, J=2.78 Hz,1 H).

Example 12N-[(2Z)-5-tert-butyl-3-{2-[(methylsulfonyl)amino]ethyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 12A(Z)—N-(3-(2-aminoethyl)-5-tert-butylthiazol-2(3H)-ylidene)-5-chloro-2-methoxybenzamide

A solution of Example 10B (0.38 g, 0.8 mmol) in CH₂Cl₂ (5 mL) wastreated with 1 mL of trifluoroacetic acid and stirred at roomtemperature for 3 hours. The solvent was removed and the concentrate waspurified by flash chromatography (SiO₂, eluting with a gradient from 0to 15% methanol in CH₂Cl₂ (0.1% NH₄OH) in 240 mL then isocratic for 300mL) to provide the title compound (0.29 g, 0.79 mmol, 97% yield). ESIm/z 368.0 (M+H)⁺. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.33 (s, 9 H)3.23-3.38 (m, J=5.09 Hz, 2 H) 3.79 (s, 3 H) 4.27-4.47 (m, J=5.76, 5.76Hz, 2 H) 7.13 (d, J=8.81 Hz, 1 H) 7.26 (s, 1 H) 7.47 (dd, J=8.82, 2.71Hz, 1 H) 7.64 (d, J=2.71 Hz, 1 H) 7.95 (s, 2 H).

Example 12BN-[(2Z)-5-tert-butyl-3-{2-[(methylsulfonyl)amino]ethyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

A solution of Example 12A (0.29 g, 0.79 mmol) in tetrahydrofuran (10 mL)was treated with methanesulfonyl chloride (0.6 mL, 0.79 mmol) andtriethylamine (0.33 mL, 0.24 mmol) and stirred at room temperature for 1hour. The mixture was diluted with ethyl acetate, washed with water,brine, dried with MgSO₄, filtered, and concentrated. The residue waspurified by flash chromatography (SiO₂, eluting with a gradient from 0to 100% ethyl acetate in hexane over 600 mL then isocratic for 300 mL)to provide the title compound (0.28 g, 0.63 mMol, 80% yield). MS(DCI/NH₃) m/z 446.1 (M+H)⁺. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.36 (s, 9 H)2.78 (s, 3 H) 3.62 (ddd, J=6.94, 5.55, 4.16 Hz, 2 H) 3.92 (s, 3 H)4.33-4.39 (m, 2 H) 5.80 (t, J=5.35 Hz, 1 H) 6.70 (s, 1 H) 6.93 (d,J=9.12 Hz, 1 H) 7.35 (dd, J=9.12, 2.78 Hz, 1 H) 7.89 (d, J=2.78 Hz, 1H).

Example 13N-[(2Z)-5-tert-butyl-3-{2-[(ethylsulfonyl)(methyl)amino]ethyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

Example 10D (0.17 g, 0.45 mmol), ethanesulfonyl chloride (98% 0.043 mL,0.45 mmol), and triethylamine (0.19 mL, 1.35 mmol) were mixed in 5 mL oftetrahydrofuran and stirred at room temperature for 1 hour. The reactionwas diluted with 100 mL ethyl acetate, washed with water, brine, driedwith MgSO₄, filtered, and concentrated. The concentrate was purified byflash chromatography (SiO₂, eluting with a gradient from 0 to 60% ethylacetate in hexane over 600 mL then isocratic for 300 mL) to provide thetitle compound (0.12 g, 0.25 mMol, 57% yield). MS (DCI/NH₃) m/z 474.2(M+H)⁺. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.32 (t, J=7.46 Hz, 3 H) 1.35 (s,9 H) 2.85 (s, 3 H) 2.96 (q, J=7.46 Hz, 2 H) 3.62-3.68 (m, 2 H) 3.91 (s,3 H) 4.37 (t, J=6.44 Hz, 2 H) 6.75 (s, 1 H) 6.92 (d, J=8.82 Hz, 1 H)7.34 (dd, J=8.82, 3.05 Hz, 1 H) 8.00 (d, J=2.71 Hz, 1 H).

Example 145-chloro-N-[(2Z)-3-[(6-fluoropyridin-3-yl)methyl]-5-methyl-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamideExample 14A 2-fluoro-5-(methylsulfonylmethyl)pyridine

(6-Fluoropyridin-3-yl)methanol (215 mg, 1.69 mmol) in CH₂Cl₂ (10 mL)containing triethylamine (354 μL, 2.54 mmol) was treated withmethanesulfonyl chloride (291 mg, 2.54 mmol) dropwise at 0° C., stirredat 0° C. for 30 min, diluted with water, and extracted with CH₂Cl₂ (2×10mL). The combined organic extract was dried (MgSO₄), filtered, andconcentrated to afford a crude oil.

Example 14B5-chloro-N-[(2Z)-3-[(6-fluoropyridin-3-yl)methyl]-5-methyl-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide

The product from Example 18 A (125 mg, 0.44 mmol) intetrahydrofuran/N,N-dimethylformamide (1:2) (5 mL) was treated with NaH(60%, 35 mg, 0.88 mmol), stirred for min at room temperature, and thentreated with Example 14A (318 mg, 1.69 mmol). The mixture was heated at75° C. for 12 hrs. After cooling, the mixture was diluted with water,and extracted with ethyl acetate. The organic extract was dried (MgSO₄),filtered, and concentrated. The concentrate was purified by reversephase HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 μm particlesize) using a gradient of 10% to 100% acetonitrile:0.1% aqueoustrifluoroacetic acid over 8 minutes (10 minutes run time) at a flow rateof 40 mL/minutes) to afford 24 mg (14%) of the title compound. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 2.27 (s, 3 H) 3.80 (s, 3 H) 5.38 (s, 2 H) 7.12(d, J=8.85 Hz, 1 H) 7.21 (dd, J=8.54, 2.75 Hz, 1 H) 7.46 (dd, J=8.85,2.75 Hz, 2 H) 7.64 (d, J=2.75 Hz, 1 H) 8.03 (td, J=8.24, 2.75 Hz, 1 H)8.37 (d, J=2.14 Hz, 1 H); MS (ESI) m/z 392 (M+H)⁺.

Example 15N-[(2Z)-3-[(2R)-azetidin-2-ylmethyl]-5-tert-butyl-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 15A (R)-tert-butyl 2-(tosyloxymethyl)azetidine-1-carboxylate

Commercially available (R)-tert-butyl2-(hydroxymethyl)azetidine-1-carboxylate (1.8 g, 9.61 mmol) in pyridinewas treated with p-toluenesulfonyl chloride (1.83 g, 9.61 mmol). Thereaction mixture was stirred at room temperature for 20 h then pouredinto water and extracted with ethyl acetate. The ethyl acetate layer waswashed with water (3×75 mL) and then dried (MgSO₄), filtered, andconcentrated in vacuo to afford the titled compound. MS (DCI) m/z 342(M+H)⁺.

Example 15B (S,Z)-tert-butyl2-((5-tert-butyl-2-(5-chloro-2-methoxybenzoylimino)thiazol-3(2H)-yl)methyl)azetidine-1-carboxylate

To a solution of Example 4C (0.4 g, 1.23 mmol) in N,N-dimethylformamide(20 mL) at 0° C. was added sodium hydride (60% dispersion in mineraloil, 0.049 g, 10.3 mmol). The reaction mixture was stirred for 30 min.and then treated with Example 15A (0.42 g, 1.23 mmol). The resultingmixture was stirred at room temperature for 18 hr, poured into water(100 mL) and extracted with ethyl acetate (2×100 mL). The organics werewashed with water and brine (2×100 mL), dried over MgSO₄, filtered, andconcentrated. The residue was purified by flash chromatography using anAnalogix® Intelliflash280 ™ (SiO₂, 0-50% ethyl acetate in hexanes) toafford the title compound (345 mg, 56% yield). MS (DCI) m/z 494 (M+H)⁺.

Example 15CN-[(2Z)-3-[(2R)-azetidin-2-ylmethyl]-5-tert-butyl-1,3-thiazol-2(3H)—)-ylidene]-5-chloro-2-methoxybenzamide

A solution of Example 15B (295 mg, 0.6 mmol) in CH₂Cl₂ (5 mL) wastreated with trifluoroacetic acid (1 mL) and the reaction mixture wasstirred at room temperature for 48 hrs, concentrated on the rotovap andthe residue was partitioned between ethyl acetate and saturated NaHCO₃.The organic layer was washed with brine, dried (MgSO₄), filtered, andconcentrated in vacuo. The residue was purified by flash chromatographyusing an Analogix® Intelliflash280 ™ (SiO₂, 0-15% methanol in CH₂Cl₂) toafford the title compound (160 mg, 68% yield). MS (DCI) m/z 394 (M+H)⁺.¹H NMR (300 MHz, DMSO -d₆) δ ppm 1.17-1.27 (m, 2 H), 1.28-1.35 (s, 9 H),2.05-2.19 (m, 1 H), 2.19-2.34 (m, 1 H), 3.45-3.61 (m, 1 H), 3.72-3.82(m, 3 H), 4.20-4.35 (m, 3 H), 7.11 (d, J=8.7 Hz, 1 H), 7.30 (s, 1 H),7.45 (dd, J=8.7, 2.8 Hz, 1 H), 7.61 (d, J=2.8 Hz, 1 H). MS (DCI) m/z 394(M+H)⁺.

Example 165-chloro-N-[(2Z)-5-chloro-3-(1,3-thiazol-4-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamideExample 16A N-(5-chlorothiazol-2-yl)-5-chloro-2-methoxybenzamide

Commercially available 5-chlorothiazol-2-amine and Example 3D wereprocessed using the method described for Example 4C to afford the titlecompound. MS (DCI) m/z 304 (M+H)⁺.

Example 16B5-chloro-N-[(2Z)-5-chloro-3-(1,3-thiazol-4-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide

A mixture of Example 16A (1001 mg, 3.33 mmol), commercially available4-(chloromethyl)thiazole (574 mg, 3.33 mmol), potassium t-butoxide (354mg, 3.33 mmol) and tetrabutylammonium iodide (492 mg, 1.33 mmol) inanhydrous toluene (30 mL)/dioxane (10 mL) was refluxed for 15 h. Themixture was then cooled to room temperature, washed with water, brine,dried with anhydrous MgSO₄, filtered, and concentrated under reducedpressure. The residue was purified using an Analogix® Intelliflash280™(SiO₂, 0-70% ethyl acetate in hexanes) to afford the title compound. 800mg, 60% yield. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.79 (s, 3 H), 5.54 (s, 2H), 7.13 (d, J=8.7 Hz, 1 H), 7.49 (dd, J=8.7, 2.8 Hz, 1 H), 7.70 (dd,J=16.3, 2.4 Hz, 2 H), 7.91 (s, 1 H), 9.10 (d, J=2.0 Hz, 1 H). MS (DCI)m/z 401 (M+H)⁺; Anal. Calculated for C₁₅H₁₁Cl₂N₃O₂S₂: C, 45.01; H, 2.77;N, 10.50. Found: C, 44.83; H, 2.71; N, 10.16.

Example 17N-[(2Z)-5-bromo-3-(1,3-thiazol-4-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 17A N-(5-bromothiazol-2-yl)-5-chloro-2-methoxybenzamide

Commercially available 5-bromothiazol-2-amine and Example 3D wereprocessed using the method described for Example 4C to afford the titlecompound. MS (DCI) m/z 348 (M+H)⁺.

Example 17BN-[(2Z)-5-bromo-3-(1,3-thiazol-4-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

A mixture of Example 17A (1001 mg, 3.33 mmol) and commercially available4-(bromomethyl)thiazole were processed using the method described forExample 16B to afford the title compound (660 mg, 52% yield). ¹H NMR(300 MHz, DMSO-d₆) δ ppm 3.78 (s, 3 H), 5.54 (s, 2 H), 7.12 (d, J=9.2Hz, 1 H), 7.49 (dd, J=8.8, 2.7 Hz, 1 H), 7.69 (dd, J=15.9, 2.4 Hz, 2 H),7.93 (s, 1 H), 9.10 (d, J=2.0 Hz, 1 H) MS (DCI) m/z 445 (M+H)⁺; Anal.Calculated for C₁₅H₁₁BrClN₃O₂S₂: C, 40.51; H, 2.49; N, 9.45. Found: C,40.85; H, 2.90; N, 9.62.

Example 185-chloro-2-methoxy-N-[(2Z)-5-methyl-3-(1,3-thiazol-4-ylmethyl)-1,3-thiazol-2(3H)-ylidene]benzamideExample 18A 5-chloro-2-methoxy-N-(5-methylthiazol-2-yl)benzamide

Commercially available 5-methylthiazol-2-amine and Example 3D wereprocessed using the method described for Example 4C to afford the titlecompound. MS (DCI) m/z 283 (M+H)⁺.

Example 18B5-chloro-2-methoxy-N-[(2Z)-5-methyl-3-(1,3-thiazol-4-ylmethyl)-1,3-thiazol-2(3H)-ylidene]benzamide

To a solution of Example 18A (2.65 g, 9.4 mmol) in N,N-dimethylformamide(20 mL) at 0° C. was added sodium hydride (60% dispersion in mineraloil, 0.247 g, 10.3 mmol). The reaction mixture was stirred for 30 min.and then treated with commercially available 4-(chloromethyl)thiazole(1.25 g, 9.4 mmol). The resulting mixture was stirred at roomtemperature for 18 h, poured into water (100 mL) and extracted withethyl acetate (2×100 mL). The organics were washed with water, brine(2×100 mL), dried over MgSO₄, filtered, and concentrated. The residuewas purified by using an Analogix® Intelliflash280 ™ (SiO₂, 0-50% ethylacetate in hexanes) to afford the title compound (2.56 g, 72% yield). ¹HNMR (300 MHz, DMSO-d₆) δ ppm 2.28 (s, 3 H), 3.77 (s, 3 H), 5.50 (s, 2H), 7.10 (d, J=8.7 Hz, 1H), 7.31 (d, J=1.6 Hz, 1 H), 7.38-7.52 (m, 2 H),7.63 (dd, J=14.5, 2.6 Hz, 1 H), 9.09 (d, J=2.0 Hz, 1 H). MS (DCI) m/z398 (M+H)⁺; MS (DCI) m/z 380 (M+H)⁺. Anal. Calculated forC₁₆H₁₄ClN₃O₂S₂: C, 50.59; H, 3.71; N, 11.06. Found: C, 50.57; H, 3.02;N, 11.03.

Example 19N-[(2Z)-5-tert-butyl-3-(1,3-thiazol-4-ylmethyl)-1,3,4-thiadiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

A mixture of Example 6A (489 mg, 1.5 mmol), commercially available4-(chloromethyl)thiazole (200 mg, 1.5 mmol), potassium carbonate (415mg, 3.0 mmol), tetrabutylammonium iodide (15 mg, 0.04 mmol),tetrabutylammonium hydrogensulfate (15 mg, 0.04 mmol) andtetraethylammonium iodide (15 mg, 0.05 mmol) in anhydrous toluene (50mL) was refluxed for 15 h. The mixture was then cooled to roomtemperature, washed with water, brine, dried with anhydrous MgSO₄,filtered, and concentrated under reduced pressure. The residue waspurified by using an Analogix® Intelliflash280™ (SiO₂, 0-60% ethylacetate in hexanes) to afford the title compound (300 mg, 47% yield). ¹HNMR (300 MHz, DMSO-d₆) δ ppm 1.37 (s, 9 H), 3.78 (s, 3 H), 5.69 (s, 2H), 7.13 (d, J=9.2 Hz, 1 H), 7.49 (dd, J=8.8, 2.7 Hz, 1 H), 7.61 (d,J=2.0 Hz, 1 H), 7.71 (d, J=3.1 Hz, 1 H), 9.08 (d, J=2.0 Hz, 1 H) MS(DCI) m/z 423 (M+H)⁺. Anal. Calculated for C₁₈H₁₉ClN₄O₂S₂: C, 51.12; H,4.53; N, 13.25. Found: C, 50.85; H, 4.32; N, 13.11.

Example 202,5-dichloro-N-[(2Z)-5-methyl-3-[(2-methyl-1,3-thiazol-4-yl)methyl]-1,3-thiazol-2(3H)-ylidene]benzamideExample 20A 2,5-dichloro-N-(5-methylthiazol-2-yl)benzamide

To a solution of 5-methylthiazole-2-amine (Aldrich, 1.0 g, 8.76 mmol) intetrahydrofuran (10 mL) was added 2,5-dichlorobenzoic acid (Aldrich)(2.01 g, 10.51 mmol), triethylamine (2.93 mL, 21.02 mmol), and1-propanephosphonic acid cyclic anhydride (Aldrich, 50% solution inethyl acetate, 6.19 mL, 10.51 mmol). The reaction mixture was stirred at22° C. for 14 h., cooled, and quenched with saturated aqueous NaHCO₃ (20mL). The aqueous layer was extracted with ethyl acetate (2×40 mL). Thecombined organic extracts were dried over anhydrous Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified bycolumn chromatography using an Analogix® Intelliflash280 ™ (SiO₂, 0-100%ethyl acetate in hexanes) to afford 1.99 g of the title compound. MS(ESI⁺) m/z 287 (M+H)⁺.

Example 20B2,5-dichloro-N-[(2Z)-5-methyl-3-[(2-methyl-1,3-thiazol-4-yl)methyl]-1,3-thiazol-2(3H)-ylidene]benzamide

To a solution of Example 20A (0.6 g, 2.1 mmol) inN,N-dimethylformamide/tetrahydrofuran (1:4, 20 mL) were added sodiumhydride (60% dispersion in mineral oil, 0.1 g, 2.5 mmol),tetrabutylammonium iodide (0.09, 0.23 mmol) and commercially available4-(chloromethyl)-2-methylthiazole (Maybridge, 0.37 g, 2.5 mmol). Thereaction mixture was stirred at 80° C. for 16 hours, cooled, dilutedwith ethyl acetate (20 mL) and quenched with saturated aqueous NaHCO₃(20 mL). The aqueous layer was extracted with ethyl acetate (2×20 mL).The combined organic layers were washed with water (1×25 mL), dried overanhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by column chromatography using an Analogix®Intelliflash280 ™ (SiO₂, 0-50% ethyl acetate in hexanes) to afford thetitle compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.30 (s, 3 H), 2.63 (s,3 H), 5.42 (s, 2 H), 7.34-7.39 (m, 2 H), 7.51 (s, 1 H), 7.52 (s, 1 H),7.88 (t, J=1.5 Hz, 1 H); MS (ESI⁺) m/z 398 (M+H)⁺; Anal. Calculated forC₁₆H₁₃Cl₂ N30S₂ 0.75H₂O: C, 48.24; H, 3.29; N, 10.55. Found: C, 46.35;H, 3.46; N, 9.97.

Example 215-chloro-2-methoxy-N-[(2Z)-5-methyl-3-[(2-methyl-1,3-thiazol-4-yl)methyl]-1,3-thiazol-2(3H)-ylidene]benzamide

Example 18A, sodium hydride (60% dispersion in mineral oil),tetrabutylammonium iodide and commercially available4-(chloromethyl)-2-methylthiazole (Maybridge) were processed using themethod described in Example 20B to afford the title compound. ¹H NMR(300 MHz, dimethylsulfoxide-d₆) δ ppm 2.28 (s, 3 H), 2.63 (s, 3 H), 3.78(s, 3 H), 5.38 (s, 2 H), 7.10 (d, J=9.1 Hz, 1 H), 7.29 (d, J=1.2 Hz,1H), 7.35 (s, 1 H), 7.44 (dd, 1 H), 7.68 (d, J=2.8 Hz, 1 H); MS (ESI⁺)m/z 394 (M+H)⁺.

Example 225-chloro-2-methoxy-N-[(2Z)-5-methyl-3-(1,3-thiazol-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]benzamide

Example 18A, sodium hydride (60% dispersion in mineral oil),tetrabutylammonium iodide and commercially available2-(chloromethyl)thiazole (Chembridge) were processed using the methoddescribed in Example 20B to afford the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 2.29 (s, 3H), 3.77 (s, 3H), 5.68 (s, 2H), 7.10 (d, J=8.8Hz, 1H), 7.40 (d, J=1.4 Hz, 1H), 7.45 (dd, J=8.8, 3.1 Hz, 1H), 7.71-7.76(m, 2H), 7.76-7.85 (m, 1 H); MS (ESI⁺) m/z 380 (M+H)⁺; Anal. Calculatedfor C₁₆H₁₄ClN₃O₂S₂: C, 50.59; H, 3.71; N, 11.06. Found: C, 50.40; H,3.45; N, 11.00.

Example 235-chloro-2-methoxy-N-[(2Z)-5-methyl-3-[(4-methyl-1,3-thiazol-2-yl)methyl]-1,3-thiazol-2(3H)-ylidene]benzamide

Example 18A, sodium hydride (60% dispersion in mineral oil),tetrabutylammonium iodide and commercially available2-(chloromethyl)-4-methylthiazole (Chembridge) were processed using themethod described in Example 20B to afford the title compound. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 2.29 (s, 3 H), 2.34 (s, 3 H), 3.77 (s, 3 H),5.61 (s, 2 H), 7.11 (d, J=8.7 Hz, 1 H), 7.25 (d, J=1.2 Hz, 1 H), 7.40(d, J=1.6 Hz, 1 H), 7.46 (dd, J=8.7, 2.8 Hz, 1 H), 7.76 (d, J=2.8 Hz, 1H); MS (ESI⁺) m/z 394 (M+H)⁺; Anal. Calculated for C₁₇H₁₆ClN₃O₂S₂: C,51.83; H, 4.09; N, 10.67. Found: C, 51.88; H, 3.80; N, 10.53.

Example 245-chloro-N-[(2Z)-3-[(6-chloropyridin-3-yl)methyl]-5-methyl-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide

Example 18A, sodium hydride (60% dispersion in mineral oil), andcommercially available 2-chloro-5-chloromethylpyridine were processedusing the method described in Example 20B to afford the title compound.¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.27 (s, 3 H), 3.79 (s, 3 H), 5.38 (s, 2H), 7.12 (d, J=8.8 Hz, 1 H), 7.42-7.44 (m, 1 H), 7.44-7.49 (m, 1H),7.51-7.58 (m, J=8.5 Hz, 1 H), 7.62 (d, J=3.1 Hz, 1 H), 7.86 (dd, J=8.1,2.4 Hz, 1 H), 8.46-8.58 (m, 1 H); MS (ESI) m/z 408 (M+H)⁺

Example 255-chloro-2-methoxy-N-[(2Z)-5-methyl-3-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-1,3-thiazol-2(3H)-ylidene]benzamide

Example 18A, sodium hydride (60% dispersion in mineral oil), andcommercially available 3-(chloromethyl)-6-(trifluoromethyl)pyridine wereprocessed using the method described in Example 20B to afford the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.29 (s, 3 H), 3.76 (s, 3 H),5.48 (s, 2 H), 7.08 (s, 1 H), 7.34 (d, J=1.4 Hz, 1 H), 7.44 (dd, J=8.8,2.7 Hz, 1 H), 7.57-7.67 (m, 2 H), 8.41-8.62 (m, 2 H); MS (ESI) m/z 442(M+H)⁺

Example 26N-[(2Z)-5-tert-butyl-3-(1,3-thiazol-4-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

To a solution of Example 4C (0.75 g, 2.31 mmol) inN,N-dimethylformamide/tetrahydrofuran (1:4, 20 mL) were added potassiumtert-butoxide (0.77 g, 6.93 mmol), tetrabutylammonium iodide (0.09, 0.23mmol) and the commercially available HCl salt of4-(chloromethyl)thiazole (TCI-US, 0.59 g, 3.46 mmol). The reactionmixture was stirred at 80° C. for 16 hours, cooled, diluted with ethylacetate (20 mL) and quenched with saturated aqueous NaHCO₃ (20 mL). Theaqueous layer was extracted with ethyl acetate (2×20 mL). The combinedorganic layers were washed with water (1×25 mL), dried over anhydrousNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by column chromatography using an Analogix® Intelliflash280™ (SiO₂, 0-100% ethyl acetate in hexanes) to afford the title compound.¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.32 (s, 9 H), 3.76 (s, 3 H), 5.49 (s, 2H), 7.09 (d, J=9.2 Hz, 1 H), 7.36 (s, 1 H), 7.44 (dd, J=9.0, 2.9 Hz, 1H), 7.57 (d, J=2.0 Hz, 1 H), 7.61 (d, J=3.1 Hz, 1 H), 9.10 (d, J=2.0 Hz,1 H); MS (ESI) m/z 422 (M+H)⁺; Anal. Calculated for C₁₉H₂₀ClN₃O₂S₂: C,54.08; H, 4.78; N, 9.96. Found: C, 54.10; H, 4.62; N, 9.81.

Example 272-ethoxy-N-[(2Z)-5-methyl-3-[3-(1H-pyrrol-1-yl)propyl]-1,3-thiazol-2(3H)-ylidene]benzamideExample 27A 3-(3-(1H-pyrrol-1-yl)propyl)-5-methylthiazol-2(3H)-imine

A mixture of 2-amino-5-methylthiazole (0.55 g, 4.8 mmol) and1-(3-bromopropyl)pyrrole (TCI-US, 1.0 g, 5.3 mmol) was warmed to 85° C.and was stirred for 2 h. The mixture was then cooled to ambienttemperature and was purified by flash column chromatography (SiO₂, 10%CH₃OH in ethyl acetate then 9:1:0.1 CH₂Cl₂:CH₃OH:NH₄OH) to give thetitle compound (0.86 g, 3.9 mmol, 81% yield). MS (DCI/NH₃) m/z 222(M+NH₄)⁺.

Example 27B2-ethoxy-N-[(2Z)-5-methyl-3-[3-(1H-pyrrol-1-yl)propyl]-1,3-thiazol-2(3H)-ylidene]benzamide

To a solution of the product of Example 27A (0.22 g, 1.0 mmol) intetrahydrofuran (15 mL) and N,N-dimethylformamide (2 mL) was addedtriethyl amine (0.42 mL, 3 mmol) followed by 2-ethoxybenzoyl chloride(0.25 g, 1.3 mmol). This mixture was stirred at ambient temperature for18 h then was concentrated under reduced pressure. The residue wasdiluted with 5 mL saturated aqueous NH₄Cl, 2 mL H₂O, and 5 mL ethylacetate. The layers were separated and the aqueous layer was extractedwith 3×5 mL ethyl acetate. The combined organics were dried overanhydrous Na₂SO₄, filtered, concentrated under reduced pressure. Theconcentrate was purified by column chromatography (SiO₂, 50% hexanes inethyl acetate) to give the title compound (0.22 g, 0.6 mmol, 60% yield).¹H NMR (300 MHz, CD₃OD) δ ppm 1.37 (t, J=7.0 Hz, 3 H), 2.24-2.38 (m, 2H), 2.31 (d, J=1.4 Hz, 3 H), 3.98 (t, J=6.8 Hz, 2 H), 4.10 (q, J=7.0 Hz,2 H), 4.18 (dd, J=7.1 Hz, 2 H), 6.03 (t, J=2.2 Hz, 2 H), 6.70 (t, J=2.0Hz, 2 H), 6.93-7.00 (m, 2 H), 7.04 (d, J=8.1 Hz, 1 H), 7.39 (ddd, J=8.4,7.4, 1.9 Hz, 1 H), 7.77 (dd, J=7.6, 1.9 Hz, 1 H); MS (DCI/NH₃) m/z 370(M+H)⁺; Anal. calculated for C₂₀H₂₃N₃O₂S: C, 65.01; H, 6.27; N, 11.37.Found: C, 64.66; H, 6.35; N, 11.35.

Example 285-chloro-2-methoxy-N-[(2Z)-5-methyl-3-[3-(1H-pyrrol-1-yl)propyl]-1,3-thiazol-2(3H)-ylidene]benzamide

To the product of Example 27A (0.25 g, 1.13 mmol) in tetrahydrofuran (15mL) and N,N-dimethylformamide (2 mL) was added triethyl amine (0.47 mL,3.4 mmol) followed by Example 3D (1.5 mmol). This mixture was warmed to45° C. and was allowed to stir for 2 h then was allowed to cool toambient temperature and was stirred for an additional 72 h. The mixturewas concentrated under reduced pressure and the residue was diluted with5 mL saturated aqueous NH₄Cl, 2 mL H₂O, and 5 mL ethyl acetate. Thelayers were separated and the aqueous layer was extracted with 3×5 mLethyl acetate. The combined organics were dried over anhydrous Na₂SO₄,filtered, and concentrated under reduced pressure. The concentrate waspurified by column chromatography (SiO₂, 50% hexanes in ethyl acetate)to give the title compound (0.25 g, 0.64 mmol, 57% yield). ¹H NMR (300MHz, CD₃OD) δ ppm 2.26-2.38 (m, 2 H), 2.32 (d, J=1.0 Hz, 3 H), 3.83 (s,3 H), 3.98 (t, J=6.8 Hz, 2 H), 4.18 (dd, J=7.1 Hz, 2 H), 6.04 (t, J=2.2Hz, 2 H), 6.70 (t, J=2.2 Hz, 2 H), 7.00 (q, J=1.1 Hz, 1 H), 7.07 (d,J=8.8 Hz, 1 H), 7.40 (dd, J=9.0, 2.9 Hz, 1 H), 7.81 (d, J=2.7 Hz, 1 H);MS (DCI/NH₃) m/z 390 (M+H)⁺; Anal. calculated for C₁₉H₂₀ClN₃O₂S: C,58.53; H, 5.17; N, 10.78. Found: C, 58.28; H, 5.13; N, 10.59.

Example 29N-[(2Z)-5-tert-butyl-3-[(2S)-pyrrolidin-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 29A (S)-tert-butyl2-((5-tert-butyl-2-iminothiazol-3(2H)-yl)methyl)pyrrolidine-1-carboxylate

To a solution of 3,3-dimethylbutanal (130 mg, 1.30 mmol) in acetonitrile(8 mL) was added molecular sieves (4A beads, 8-12 mesh, 0.7 g) and(S)-tert-butyl 2-(aminomethyl)pyrrolidine-1-carboxylate (260 mg, 1.30mmol). The mixture was stirred for 12 hr at room temperature, filtered,and washed with acetonitrile (5 mL). To this solution was addedpotassium thiocyanate (168 mg, 1.72 mmol) and the temperature wasadjusted at 50° C. The reaction was stirred until all solids weredissolved then iodine (659 mg, 2.6 mmol) was added. The reaction mixturewas stirred at 50° C. for another 12 hr, cooled to room temperature, andstirred with 20% sodium metabisulfite for 1 hr. The organic layer wasseparated and the aqueous layer was extracted with dichloromethane (3×10mL). The combined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure to give the title compound. Thisintermediate was used without further purification. MS (DCI/NH₃) m/z 340(M+H)⁺.

Example 29B (S,Z)-tert-butyl2-((5-tert-butyl-2-(5-chloro-2-methoxybenzoylimino)thiazol-3(2H)-yl)methyl)pyrrolidine-1-carboxylate

To a solution of crude Example 29A (850 mg, 3.00 mmol) indichloromethane (6 mL) was added triethylamine (0.419 mL, 3.00 mmol),followed by addition of Example 3D (513 mg, 2.504 mmol). The reactionwas stirred overnight and washed with water, dried (MgSO₄), filtered,and concentrated. The residue was purified by column chromatographyusing an Analogix® Intelliflash280™ (SiO₂, 0-100% ethyl acetate inhexanes) to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm1.14-1.28 (m, 9 H) 1.29 (s, 9 H) 1.52-1.64 (m, 4 H) 3.33-3.38 (m, 2 H)3.78 (s, 3 H) 3.83-3.89 (m, 1 H) 4.00-4.06 (m, 1 H) 4.30-4.40 (m, 1 H)7.07-7.11 (m, 1 H) 7.16-7.22 (m, 1 H) 7.39-7.47 (m, 1 H) 7.65-7.71 (m, 1H) MS (DCI) m/z 508 (M+H)⁺.

Example 29CN-[(2Z)-5-tert-butyl-3-[(2S)-pyrrolidin-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

To a solution of Example 29B (140 mg, 0.28 mmol.) in methanol (2 mL) wasadded hydrogen chloride in dioxane (0.5 mL, 2.000 mmol) and stirred for12 hr. The solvent was removed under reduced pressure and the residuerecrystallized from methanol:diethyl ether to provide the title compoundas a hydrogen chloride salt. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.33 (s, 9H) 1.68-1.79 (m, 1 H) 1.87-2.01 (m, 2 H) 2.03-2.12 (m, 1 H) 3.14-3.28(m, 2 H) 3.81 (s, 3 H) 3.93-4.06 (m, 1 H) 4.47 (d, J=6.44 Hz, 2 H) 7.14(d, J=9.16 Hz, 1 H) 7.45-7.50 (m, 2 H) 7.63 (d, J=2.71 Hz, 1 H) 9.29 (d,J=4.41 Hz, 2 H); MS (DCI) m/z 408 (M+H)⁺. Anal. calcd forC₂₀H₂₆ClN₃O₂S.2HCl.1.0H₂O: C, 48.15; H, 6.06; N, 8.42. Found: C, 48.00;H, 6.04; N, 8.27.

Example 30N-[(2Z)-5-tert-butyl-3-[(2S)-piperidin-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 30A (S)-tert-butyl2-((5-tert-butyl-2-iminothiazol-3(2H)-yl)methyl)piperidine-1-carboxylate

The title compound was prepared and isolated as described in Example29A, substituting (S)-tert-butyl 2-(aminomethyl)piperidine-1-carboxylatefor (S)-tert-butyl 2-(aminomethyl)pyrrolidine-1-carboxylate. MS(DCI/NH₃) m/z 354 (M+H)⁺.

Example 30B (S,Z)-tert-butyl2-((5-tert-butyl-2-(5-chloro-2-methoxybenzoylimino)thiazol-3(2H)-yl)methyl)piperidine-1-carboxylate

The title compound was prepared and purified as described in Example29B, substituting Example 30A for Example 29A. ¹H NMR (300 MHz, DMSO-d₆)δ ppm 1.14-1.28 (m, 9 H) 1.29 (s, 9 H) 1.52-1.64 (m, 4 H) 1.67-1.72 (m,2 H) 3.33-3.38 (m, 1 H) 3.78 (s, 3 H) 3.83-3.90 (m, 1 H) 4.00-4.04 (m, 1H) 4.57-4.61 (m, 1 H) 4.70-4.74 (m, 1 H) 7.07-7.11 (m, 1 H) 7.16-7.22(m, 1 H) 7.41-7.45 (m, 1 H) 7.65-7.71 (m, 1 H); MS (DCI/NH₃) m/z 522(M+H)⁺.

Example 30CN-[(2Z)-5-tert-butyl-3-[(2S)-piperidin-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

The HCl salt of the title compound was prepared and purified asdescribed in Example 29C, substituting Example 30B for Example 29B. ¹HNMR (300 MHz, DMSO-d₆) δ ppm 1.27-1.38 (s, 9 H) 1.48-1.64 (m, 3 H)1.68-1.84 (m, 3 H) 2.85 (m, 1 H) 3.26 (m, 1 H) 3.39-3.54 (m, 1 H)3.77-3.82 (m, 3 H) 4.30-4.45 (m, 2 H) 7.13 (d, J=9.12 Hz, 1 H) 7.33 (s,1H) 7.46 (dd, J=8.92, 2.97 Hz, 1 H) 7.63 (d, J=2.78 Hz, 1 H) 8.89 (m, 1H) 9.02 (m, 1 H); MS (DCI) m/z 422 (M+H)⁺. Anal. calcd forC₂₁H₂₈ClN₃O₂S*3HCl: C, 47.47; H, 5.88; N, 7.91. Found: C, 47.60; H,6.28; N, 8.00.

Example 31N-[(2Z)-5-tert-butyl-3-[(2R)-piperidin-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 31A (R)-tert-butyl2-((5-tert-butyl-2-iminothiazol-3(2H)-yl)methyl)piperidine-1-carboxylate

The title compound was prepared and isolated as described in Example29A, substituting (R)-tert-butyl 2-(aminomethyl)piperidine-1-carboxylatefor (S)-tert-butyl 2-(aminomethyl)pyrrolidine-1-carboxylate. MS(DCI/NH₃) m/z 354 (M+H)⁺.

Example 31B (R,Z)-tert-butyl2-((5-tert-butyl-2-(5-chloro-2-methoxybenzoylimino)thiazol-3(2H)-yl)methyl)piperidine-1-carboxylate

The title compound was prepared and purified as described in Example29B, substituting Example 31A for Example 29A. ¹HNMR (300 MHz, DMSO-d₆)δ ppm 1.14-1.28 (m, 9 H) 1.29 (s, 9 H) 1.52-1.64 (m, 4 H) 1.67-1.72 (m,2 H) 3.33-3.38 (m, 1 H) 3.78 (s, 3 H) 3.83-3.90 (m, 1 H) 4.00-4.04 (m, 1H) 4.57-4.61 (m, 1 H) 4.70-4.74 (m, 1 H) 7.07-7.11 (m, 1 H) 7.16-7.22(m, 1 H) 7.41-7.45 (m, 1 H) 7.65-7.71 (m, 1 H); MS (DCI/NH₃) m/z 522(M+H)⁺.

Example 31CN-[(2Z)-5-tert-butyl-3-[(2R)-piperidin-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

The HCl salt of the title compound was prepared and purified asdescribed in Example 29C, substituting Example 31B for Example 29B. ¹HNMR (300 MHz, DMSO-d₆) δ ppm 1.27-1.38 (s, 9 H) 1.48-1.64 (m, 3 H)1.68-1.84 (m, 3 H) 2.85 (dm, 1 H) 3.26 (m, 1 H) 3.39-3.54 (m, 1 H)3.77-3.80 (s, 3 H) 4.30-4.45 (m, 2 H) 7.13 (d, J=9.12 Hz, 1 H) 7.33 (s,1 H) 7.46 (dd, J=8.92, 2.97 Hz, 1 H) 7.63 (d, J=2.78 Hz, 1 H) 8.89 (m, 1H) 9.02 (m, 1 H); MS (DCI) m/z 422 (M+H)⁺. Anal. calcd forC₂₁H₂₈ClN₃O₂S.2HCl.0.5H₂O: C, 47.49; H, 6.17; N, 7.91. Found: C, 47.64;H, 6.49; N, 7.87.

Example 32N-[(2Z)-5-tert-butyl-3-{[(2S)-1-methylpyrrolidin-2-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

To a solution of Example 29C (100 mg, 0.208 mmol) in dichloromethane (2mL) and acetonitrile (2 mL) was added paraformaldehyde (63 mg, 2.098mmol), followed by addition of sodium acetate (42.6 mg, 0.520 mmol) andsodium triacetoxyhydroborate (264 mg, 1.248 mmol) and stirred for 12 hrat 50° C. The reaction was concentrated and sodium carbonate (10%, 15mL) was added to the residue and extracted with dichloromethane (3×20mL). The organics were combined, washed with brine, dried (MgSO₄),filtered, and concentrated. The residue was purified by Analogix®Intelliflash280 ™ (SiO₂, 0-10% dichloromethane in methanol) to affordthe title compound. ¹H NMR (300 MHz, CD₃OD) δ ppm 1.37-1.42 (s, 9 H)1.69-1.82 (m, 3 H) 1.89 (m, 1 H) 2.28-2.38 (m, 1 H) 2.42 (s, 3 H)2.85-2.94 (m, 1 H) 3.04-3.12 (m, 1 H) 3.86 (s, 3 H) 4.07-4.16 (m, 1 H)4.44 (dd, J=13.09, 4.76 Hz, 1 H) 7.07 (d, J=8.72 Hz, 1 H) 7.20 (s, 1 H)7.40 (dd, J=9.12, 2.78 Hz, 1 H) 7.94 (d, J=2.78 Hz, 1 H); MS (DCI) m/z422 (M+H)⁺. Anal. calcd for C₂₁H₂₈ClN₃O₂S.0.5 ethyl acetate: C, 60.21;H, 6.98; N, 9.32. Found: C, 60.08; H, 6.77; N, 9.16.

Example 33N-[(2Z)-5-tert-butyl-3-{[(2S)-1-methylpiperidin-2-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

The title compound was prepared and purified as described in Example 32,substituting Example 30C for Example 29C. ¹H NMR (300 MHz, CD₃OD) δ ppm1.25-1.35 (m, 1 H) 1.38 (s, 9 H) 1.43-1.47 (m, 1 H) 1.56-1.66 (m, 2 H)1.72-1.80 (m, 2 H) 2.21-2.27 (m, 1 H) 2.47 (s, 3 H) 2.64-2.73 (m, 1 H)2.86-2.94 (m, 1 H) 3.86 (s, 3 H) 4.06 (dd, J=13.22, 8.81 Hz, 1 H) 4.71(dd, J=13.22, 4.75 Hz, 1 H) 7.05-7.10 (m, 1 H) 7.16 (s, 1 H) 7.41 (dd,J=8.81, 2.71 Hz, 1 H) 7.97 (d, J=2.71 Hz, 1 H); MS (DCI) m/z 436 (M+H)⁺.Anal. calcd for C₂₂H₃₀ClN₃O₂S.0.1CH₂Cl₂: C, 59.72; H, 6.85; N, 9.45.Found: C, 59.69; H, 6.48; N, 9.54.

Example 34N-[(2Z)-5-tert-butyl-3-{[(2R)-1-methylpiperidin-2-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

The title compound was prepared and purified as described in Example 32,substituting Example 31C for Example 29C. ¹H NMR (300 MHz, CD₃OD) δ ppm1.25-1.34 (m, 2 H) 1.37 (s, 9 H) 1.46 (m, 1 H) 1.55-1.67 (m, 2 H)1.73-1.77 (m, 1 H) 2.20-2.29 (m, 1 H) 2.47 (s, 3 H) 2.64-2.73 (m, 1 H)2.86-2.94 (m, 1 H) 3.87 (s, 3 H) 4.06 (dd, J=13.22, 8.82 Hz, 1 H) 4.70(dd, J=13.22, 4.75 Hz, 1 H) 7.07 (d, J=8.81 Hz, 1 H) 7.15 (s, 1 H) 7.40(dd, J=8.81, 2.71 Hz, 1 H) 7.96 (d, J=2.71 Hz, 1 H); MS (DCI) m/z 436(M+H)⁺. Anal. calcd for C₂₂H₃₀ClN₃O₂S.0.1H₂O: C, 60.35H, 6.95; N, 9.60.Found: C, 60.38; H, 6.87; N, 9.22.

Example 35N-[(2Z)-5-tert-butyl-3-{[(2R)-1-ethylpiperidin-2-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

The title compound was prepared and purified as described in Example 32,substituting Example 31C for Example 29C and acetaldehyde forparaformaldehyde. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.15 (t, J=7.12 Hz, 3 H)1.28-1.43 (m, 11 H) 1.53-1.67 (m, 3 H) 1.68-1.78 (m, 1 H) 2.38-2.47 (m,1 H) 2.74-2.82 (m, 1 H) 2.88-2.96 (m, 2 H) 3.00-3.10 (m, 1 H) 3.90 (s, 3H) 3.98 (dd, J=13.22, 8.81 Hz, 1 H) 4.69 (dd, J=13.22, 4.41 Hz, 1 H)6.66 (s, 1 H) 6.90 (d, J=9.15 Hz, 1 H) 7.33 (dd, J=8.81, 2.71 Hz, 1 H)8.03 (d, J=3.05 Hz, 1 H); MS (DCI) m/z 450 (M+H)⁺.

Example 36N-[(2Z)-5-tert-butyl-3-[(3R)-piperidin-3-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 36A (R)-tert-butyl 3-(tosyloxymethyl)piperidine-1-carboxylate

To a suspension of (R)-tert-butyl3-(hydroxymethyl)piperidine-1-carboxylate (400 mg, 1.858 mmol) andpyridine (1.10 ml, 13.60 mmol) in tetrahydrofuran (5 ml) was addedp-toluenesulfonyl chloride (425 mg, 2.230 mmol) and stirred for 10 hr.To the reaction was added citric acid (4 g) and water (10 mL) andextracted with ethyl acetate (3×10 mL). The organics were combined,dried (MgSO₄), filtered, and concentrated. The residue was purified byAnalogix® Intelliflash280 ™ (SiO₂, 0-40% ethyl acetate in hexanes). ¹HNMR (300 MHz, DMSO-d₆) δ ppm 1.13-1.21 (m, 1 H) 1.23-1.31 (m, 1 H) 1.37(s, 9 H) 1.46-1.55 (m, 1 H) 1.59-1.74 (m, 2 H) 2.43 (s, 3 H) 2.68-2.83(m, 1 H) 3.28-3.32 (m, 1H), 3.67-3.73 (m, 2 H) 3.89 (d, J=6.10 Hz, 2 H)7.49 (m, 2 H) 7.76-7.81 (m, 2 H); MS (DCI) m/z 387 (M+NH₄)⁺.

Example 36B (R,Z)-tert-butyl3-((5-tert-butyl-2-(5-chloro-2-methoxybenzoylimino)thiazol-3(2H)-yl)methyl)piperidine-1-carboxylate

To a solution of Example 4C (220 mg, 0.677 mmol) in toluene (5 mL) wasadded Example 36A, followed by addition of tetrabutylammonium iodide(100 mg, 0.271 mmol), potassium t-butoxide (91 mg, 0.812 mmol) anddioxane (0.4 mL). The reaction mixture was refluxed overnight. Water (15mL) was added to the cooled reaction mixture and extracted with ethylacetate (3×15 mL). The organics were combined, washed with brine, dried(MgSO₄), filtered, and concentrated. The residue was purified byAnalogix® Intelliflash280 ™ (SiO₂, 0-30% ethyl acetate in hexanes) toprovide the title compound. ¹H NMR (300 MHz, CDCl₃) δ ppm 0.35 (s, 9 H)1.42 (s, 9 H) 1.43-1.49 (m, 1 H) 1.66-1.82 (m, 2 H) 2.12-2.20 (m, 3 H)2.83-2.89 (m, 1 H) 3.79 (dd, J=13.05, 3.56 Hz, 2 H) 3.90 (s, 3 H)3.94-4.04 (m, 1 H) 4.11-4.15 (m, 1 H) 6.65 (s, 1 H) 6.90 (d, J=8.82 Hz,1 H) 7.33 (dd, J=8.82, 2.71 Hz, 1 H) 7.96 (d, J=2.71 Hz, 1 H); MS (DCI)m/z 522 (M+H)⁺.

Example 36CN-[(2Z)-5-tert-butyl-3-[(3R)-piperidin-3-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

The HCl salt of the title compound was prepared and purified asdescribed in Example 29C, substituting Example 36B for Example 29B. ¹HNMR (300 MHz, CD₃OD) δ ppm 1.44 (s, 9 H) 1.46-1.55 (m, 1 H) 1.71-1.83(m, 1 H) 1.85-1.94 (m, 1 H) 1.97-2.08 (m, 1 H) 2.45-2.60 (m, 1 H)2.85-3.01 (m, 2 H) 3.32-3.40 (m, 1 H) 3.63-3.76 (m, 1 H) 3.99 (s, 3 H)4.37 (dd, J=7.54, 3.97 Hz, 2 H) 7.21 (d, J=8.73 Hz, 1 H) 7.50 (s, 1 H)7.55 (dd, J=8.73, 2.78 Hz, 1 H) 7.90 (d, J=2.78 Hz, 1 H); MS (DCI) m/z422 (M+H)⁺. Anal. calcd for C₂₁H₂₈ClN₃O₂S.2HCl.2H₂O: C, 47.51; H, 6.45;N, 7.91. Found: C, 47.54; H, 6.56; N, 7.93.

Example 37N-[(2Z)-5-tert-butyl-3-[(2R)-pyrrolidin-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 37A (R)-tert-butyl 2-(tosyloxymethyl)pyrrolidine-1-carboxylate

The title compound was prepared and purified as described in Example36A, substituting (R)-tert-butyl2-(hydroxymethyl)pyrrolidine-1-carboxylate for (R)-tert-butyl3-(hydroxymethyl)piperidine-1-carboxylate. ¹H NMR (300 MHz, DMSO-d₆) δppm 1.28-1.35 (m, 9 H) 1.65-1.98 (m, 4 H) 2.42 (s, 3 H) 3.09-3.24 (m, 2H) 3.79-3.85 (s, 1 H) 3.93-4.07 (m, 2 H) 7.49 (d, J=8.14 Hz, 2 H) 7.77(d, J=8.14 Hz, 2 H); MS (DCI) m/z 373 (M+NH₄)⁺.

Example 37B (R,Z)-tert-butyl2-((5-tert-butyl-2-(5-chloro-2-methoxybenzoylimino)thiazol-3(2H)-yl)methyl)pyrrolidine-1-carboxylate

The title compound was prepared and purified as described in Example36B, substituting Example 37A for Example 36A. ¹H NMR (300 MHz, CDCl₃) δppm 1.34 (s, 9 H) 1.38-1.44 (m, 1 H) 1.49 (s, 9 H) 1.75-1.91 (m, 2 H)2.03-2.13 (m, 1 H) 3.31 (d, J=6.74 Hz, 2 H) 3.90 (s, 3 H) 4.11-4.25 (m,1 H) 4.32-4.43 (m, 1 H) 4.43-4.56 (m, 1 H) 6.88-6.93 (m, 1 H) 7.33 (dd,J=8.73, 2.78 Hz, 1 H) 7.99 (s, 1 H); MS (DCI) m/z 508 (M+H)⁺.

Example 37CN-[(2Z)-5-tert-butyl-3-[(2R)-pyrrolidin-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

The HCl salt of the title compound was prepared and purified asdescribed in Example 29C, substituting Example 37B for Example 29B. ¹HNMR (300 MHz, METHANOL-d₄) δ ppm 1.42 (s, 9 H) 1.79-1.92 (m, 1 H)1.98-2.13 (m, 2 H) 2.23-2.36 (m, 1 H) 3.33-3.36 (m, 2 H) 3.92 (s, 3 H)4.04-4.16 (m, 1 H) 4.59-4.71 (m, 2 H) 7.39 (s, 1 H) 7.48 (dd, J=8.72,2.78 Hz, 1 H) 7.71 (d, J=2.78 Hz, 1 H); MS (DCI) m/z 408 (M+H)⁺.

Example 38N-[(2Z)-5-tert-butyl-3-[2-(2-oxopyrrolidin-1-yl)ethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 38A1-(2-(5-tert-butyl-2-iminothiazol-3(2H)-yl)ethyl)pyrrolidin-2-one

The title compound was prepared and isolated as described in Example29A, substituting 1-(2-aminoethyl)pyrrolidin-2-one hydrochloride (MatrixScientific) for (S)-tert-butyl 2-(aminomethyl)pyrrolidine-1-carboxylate.MS (DCI/NH₃) m/z 268 (M+H)⁺.

Example 38BN-[(2Z)-5-tert-butyl-3-[2-(2-oxopyrrolidin-1-yl)ethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

The title compound was prepared and purified as described in Example29B, substituting Example 38A for Example 29A. ¹H NMR (300 MHz, CDCl₃) δppm 1.39 (s, 9 H) 1.93-2.05 (m, 2 H) 2.37 (t, J=8.13 Hz, 2 H) 3.43 (t,J=6.94 Hz, 2 H) 3.77 (t, J=6.35 Hz, 2 H) 3.95 (s, 3 H) 4.54 (t, J=6.54Hz, 2 H) 6.97 (d, J=8.72 Hz, 1 H) 7.04 (s, 1 H) 7.45 (dd, J=9.12, 2.78Hz, 1 H) 7.95 (d, J=2.78 Hz, 1 H); MS (DCI) m/z 436 (M+H)⁺. Anal.Calculated for C₂₁H₂₆ClN₃O₃S.1.7TFA: C, 46.53; H, 4.43; N, 6.67. Found:C, 46.29; H, 4.28; N, 6.39.

Example 39N-[(2Z)-5-tert-butyl-3-[2-(2-oxopiperidin-1-yl)ethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 39A1-(2-(5-tert-butyl-2-iminothiazol-3(2H)-yl)ethyl)piperidin-2-one

The title compound was prepared and purified as described in Example29A, substituting 1-(2-aminoethyl)piperidin-2-one hydrochloride (MatrixScientific) for (S)-tert-butyl 2-(aminomethyl)pyrrolidine-1-carboxylate.MS (DCI/NH₃) m/z 282 (M+H)⁺.

Example 39BN-[(2Z)-5-tert-butyl-3-[2-(2-oxopiperidin-1-yl)ethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

The title compound was prepared and purified as described in Example29B, substituting Example 39A for Example 29A. ¹H NMR (300 MHz, CDCl₃) δppm 1.34 (s, 9 H) 1.64-1.77 (m, 4 H) 2.36 (t, J=6.27 Hz, 2 H) 3.15 (t,J=5.43 Hz, 2 H) 3.77 (t, J=6.44 Hz, 2 H) 3.91 (s, 3 H) 4.40 (t, J=6.27Hz, 2 H) 6.92 (d, J=9.16 Hz, 1 H) 7.34 (dd, J=8.82, 3.05 Hz, 1 H) 8.03(d, J=3.05 Hz, 1 H); MS (DCI) m/z 450 (M+H)⁺. Anal. Calculated forC₂₂H₂₈ClN₃O₃S.0.8H₂O: C, 56.91; H, 6.42; N, 9.05. Found: C, 57.31; H,6.33; N, 8.65.

Example 40N-[(2Z)-5-tert-butyl-3-[2-(2-oxoimidazolidin-1-ylethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 40A1-(2-(5-tert-butyl-2-iminothiazol-3(2H)-yl)ethyl)imidazolidin-2-one

The title compound was prepared and isolated as described in Example29A, substituting 1-(2-aminoethyl)imidazolidin-2-one (Matrix Scientific)for (S)-tert-butyl 2-(aminomethyl)pyrrolidine-1-carboxylate. MS(DCI/NH₃) m/z 269 (M+H)⁺.

Example 40BN-[(2Z)-5-tert-butyl-3-[2-(2-oxoimidazolidin-1-yl)ethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

The title compound was prepared as described in Example 29B,substituting Example 40A for Example 29A, and purified by reverse phaseHPLC using a Waters Sunfire C8 column (30×75 mm) eluting with a gradientof acetonitrile and 0.1% trifluoroacetic acid in water at a flow rate of50 mL/min. Fractions selected by mass spectrometry and concentrated toprovide the title compound as a trifluoroacetic acid salt. ¹H NMR (300MHz, CDCl₃) δ ppm 1.40 (s, 9 H) 3.42-3.50 (m, 2 H) 3.54-3.63 (m, 2 H)3.72 (t, J=6.27 Hz, 2 H) 3.96-4.00 (m, 3 H) 4.60 (t, J=6.10 Hz, 2 H)6.99 (d, J=8.82 Hz, 1 H) 7.18 (s, 1 H) 7.49 (dd, J=8.82, 2.71 Hz, 1 H)7.96 (d, J=2.71 Hz, 1 H); MS (DCI) m/z 437 (M+H)⁺. Anal. Calculated forC₂₀H₂₅ClN₄O₃S.2.4TFA.1H₂O: C, 40.88; H, 4.07; 7.69. Found: C, 41.16; H,3.78; N, 7.37.

Example 41(Z)—N-(5-tert-butyl-3-(2-sulfamoylethyl)thiazol-2(3H)-ylidene)-2-methoxy-5-(trifluoromethyl)benzamideExample 41A 2-(5-tert-butyl-2-iminothiazol-3(2H)-yl)ethanesulfonamide

A mixture of 3,3-dimethylbutanal (2.15 mL, 17.1 mmol), triethylamine(2.2 mL, 15.6 mmol), 2-aminoethanesulfonamide-hydrochloric acid (2.5 g,15.6 mmol), and 4 g of 4 Å molecular sieves (8-12 mesh beads) inacetonitrile (40 mL) was stirred at ambient temperature for 20 h. Thismaterial was filtered through Celite with acetonitrile (additional 25mL) then potassium thiocyanate (2.0 g, 20.7 mmol) was added and themixture was warmed to 50° C. Iodine (3.95 g, 15.6 mmol) was added andthe mixture was stirred at 50° C. for 16 h then was cooled to ambienttemperature. The mixture was stirred with 50 mL of 20% aqueous sodiummetabisulfite for 1 h then the layers were separated and the aqueouslayer was extracted with CH₂Cl₂ (3×10 mL). The combined organics weredried over anhydrous Na₂SO₄, filtered, and concentrated under reducedpressure to give the crude title compound (0.5 g, 1.9 mmol, 12.2% yield)which was carried on without further purification. MS (DCI/NH₃) m/z 264(M+H)⁺.

Example 41B(Z)—N-(5-tert-butyl-3-(2-sulfamoylethyl)thiazol-2(3H)-ylidene)-2-methoxy-5-(trifluoromethyl)benzamide

To a solution of Example 41A (0.5 g, 1.9 mmol) in tetrahydrofuran (20mL) was added triethylamine (0.80 mL, 5.7 mmol) followed by Example 1B(0.48 g, 2.0 mmol). This mixture was warmed to 50° C. and was allowed tostir for 16 h. The mixture was cooled to ambient temperature and wasquenched with saturated, aqueous NH₄Cl. The layers were separated andthe aqueous layer was extracted with ethyl acetate (3×5 mL). Thecombined organics was dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure. The crude material was purified bycolumn chromatography (SiO₂, 60% hexanes in ethyl acetate) to give thetitle compound (0.27 g, 0.58 mmol, 31% yield). ¹H NMR (300 MHz, CD₃OD) δppm 1.39 (s, 9 H), 3.69 (t, J=6.4 Hz, 2 H), 3.96 (s, 3 H), 4.66 (t,J=6.6 Hz, 2 H), 7.20 (s, 1 H), 7.25 (d, J=8.8 Hz, 1 H), 7.73 (ddd,J=8.8, 2.4, 0.7 Hz, 1 H), 8.16 (d, J=2.4 Hz, 1 H); MS (DCI/NH₃) m/z 466(M+H)⁺; Anal. calculated for C₁₈H₂₂F₃N₃O₄S₂: C, 46.44; H, 4.76; N, 9.03.Found: C, 46.38; H, 4.55; N, 8.93.

Example 42N-[(2Z)-5-tert-butyl-3-{[1-(methylsulfonyl)azetidin-3-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-5-(trifluoromethyl)benzamideExample 42A tert-butyl3-((5-tert-butyl-2-iminothiazol-3(2H)-yl)methyl)azetidine-1-carboxylate

A mixture of 3,3-dimethylbutanal (3.7 mL, 30 mmol), tert-butyl3-(aminomethyl)azetidine-1-carboxylate (Astatech, 5 g, 27 mmol), and 8 gof 4 Å molecular sieves (8-12 mesh beads) in acetonitrile (50 mL) wasstirred at ambient temperature for 72 h. The material was filteredthrough Celite with acetonitrile (additional 25 mL) then potassiumthiocyanate (3.5 g, 35 mmol) was added and the mixture was warmed to 50°C. Iodine (6.8 g, 26.8 mmol) was added and the mixture stirred at 50° C.for 16 h then was cooled to ambient temperature. The mixture was stirredwith 75 mL of 20% aqueous sodium metabisulfite for 1 h then the layerswere separated and the aqueous layer was extracted with 3×10 mL CH₂Cl₂.The combined organics were dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure to give the crude title compound(6.3 g, 19 mmol, 72% yield) which was carried on without furtherpurification. MS (DCI/NH₃) m/z 326 (M+H)⁺.

Example 42B (Z)-tert-butyl3-((5-tert-butyl-2-(2-fluoro-5-(trifluoromethyl)benzoylimino)thiazol-3(2H)-yl)methyl)azetidine-1-carboxylate

To a solution of the product of Example 42A (4.1 g, 12.5 mmol) intetrahydrofuran (40 mL) was added triethylamine (5.2 mL, 37.6 mmol)followed by 2-fluoro-5-(trifluoromethyl)benzoyl chloride (2.0 mL, 13.2mmol). This mixture was warmed to 50° C. and was allowed to stir for 90min then the mixture was cooled to ambient temperature and was stirredfor 16 h. The mixture was quenched with saturated, aqueous NH₄Cl (20 mL)and diluted with ethyl acetate (20 mL). The layers were separated andthe aqueous layer was extracted with ethyl acetate (3×10 mL). Thecombined organics were dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure. The crude material was purified bycolumn chromatography (SiO₂, 60% hexanes in ethyl acetate) to give thetitle compound (5.2 g, 10.0 mmol, 80% yield). MS (DCI/NH₃) m/z 516(M+H)⁺.

Example 42C(Z)—N-(3-(azetidin-3-ylmethyl)-5-tert-butylthiazol-2(3H)-ylidene)-2-fluoro-5-(trifluoromethyl)benzamide

A mixture of the product of Example 42B (5.2 g, 10.0 mmol) andtrifluoroacetic acid (15.4 mL, 200 mmol) in CH₂Cl₂ (20 mL) was stirredat ambient temperature for 2 h then was concentrated under reducedpressure to give the crude trifluoroacetic acid salt of the titlecompound. This material was carried on without purification. MS(DCI/NH₃) m/z 416 (M+H)⁺.

Example 42D(Z)—N-(5-tert-butyl-3-((1-(methylsulfonyl)azetidin-3-yl)methyl)thiazol-2(3H)-ylidene)-2-fluoro-5-(trifluoromethyl)benzamide

To a solution of the product of Example 42C in tetrahydrofuran (20 mL)was added triethyl amine (5.6 mL, 40.0 mmol) followed by methanesulfonylchloride (1.6 mL, 20.0 mmol). This mixture was stirred at ambienttemperature for 16 h. The mixture was quenched with saturated, aqueousNaHCO₃ (5 mL) and was diluted with ethyl acetate (5 mL). The layers wereseparated and the aqueous layer was extracted with ethyl acetate (3×5mL). The combined organics were dried over anhydrous Na₂SO₄, filtered,concentrated under reduced pressure and purified via columnchromatography (SiO₂, 50% hexanes/ethyl acetate then 100% ethyl acetatethen 9:1:0.1 ethyl acetate:methanol:triethyl amine) to give the titlecompound (3.2 g, 6.5 mmol, 65% yield). MS (DCI/NH₃) m/z 494 (M+H)⁺.

Example 42EN-[(2Z)-5-tert-butyl-3-{[1-(methylsulfonyl)azetidin-3-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-5-(trifluoromethyl)benzamide

To a solution of (S)-(1-methylpyrrolidin-2-yl)methanol (0.36 mL, 3.0mmol) in tetrahydrofuran (15 mL) at ambient temperature was addedpotassium tert-butoxide (0.51 g, 4.5 mmol). The mixture was stirred atambient temperature for 20 min then the product of Example 42D (0.74 g,1.5 mmol) in 5 mL tetrahydrofuran was added via cannula. The mixture wasstirred for 3 h at ambient temperature then was quenched with saturated,aqueous NaHCO₃ (10 mL) and diluted with ethyl acetate (10 mL). Thelayers were separated and the aqueous layer was extracted with ethylacetate (3×10 mL). The combined organics were dried over anhydrousNa₂SO₄, filtered, and concentrated under reduced pressure. The crudematerial was purified via column chromatography SiO₂ (50% hexanes/ethylacetate then 100% ethyl acetate then 9:1:0.1 ethylacetate/methanol/triethyl amine) to give the title compound (0.64 g, 1.1mmol, 73% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm 1.36 (s, 9 H) 1.63-1.93(m, 3 H) 2.18-2.37 (m, 1 H) 2.47 (s, 3 H) 2.74-2.86 (m, 1 H) 2.82 (s, 3H) 3.02-3.14 (m, 1 H) 3.16-3.34 (m, 1 H) 3.81 (dd, J=8.1, 5.8 Hz, 2 H)3.93-4.19 (m, 5 H) 4.39 (d, J=7.5 Hz, 2 H) 6.62 (s, 1 H) 7.04 (d, J=8.7Hz, 1 H) 7.60 (dd, J=8.3, 2.4 Hz, 1 H) 8.10 (d, J=2.4 Hz, 1 H); MS(DCI/NH₃) m/z 589 (M+H)⁺; Anal. calculated for C₂₆H₃₅F₃N₄O₄S₂: Calc: C,53.04; H, 5.99; N, 9.52. Found: 53.13; H, 5.96; N, 9.42.

Example 435-chloro-2-methoxy-N-[(2Z)-5-methyl-3-{3-[(methylsulfonyl)amino]propyl}-1,3-thiazol-2(3H)-ylidene]benzamideExample 43A tert-butyl3-(2-imino-5-methylthiazol-3(2H)-yl)propylcarbamate

A mixture of 2-amino-5-methylthiazole (0.58 g, 5.0 mmol) and3-(Boc-amino)propyl bromide (1.2 g, 5.0 mmol) was warmed to 85° C. andwas allowed to stir for 4 h. The mixture was cooled to ambienttemperature and was purified via column chromatography (SiO₂, 9:1:0.1CH₂Cl₂:methanol:ammonium hydroxide) to give the title compound (0.96 g,3.5 mmol, 70% yield). MS (DCI/NH₃) m/z 272 (M+H)⁺.

Example 43B (Z)-tert-butyl3-(2-(5-chloro-2-methoxybenzoylimino)-5-methylthiazol-3(2H)-yl)propylcarbamate

To a solution of the product of Example 43A (0.96 g, 3.5 mmol) intetrahydrofuran (25 mL) was added triethylamine (1.5 mL, 10.6 mmol)followed by Example 3D in tetrahydrofuran (5 mL) via cannula. Thismixture was warmed to 50° C. and was allowed to stir for 4 h. Themixture was cooled to ambient temperature and was quenched withsaturated, aqueous NH₄Cl (5 mL). The layers were separated and theaqueous layer was extracted with ethyl acetate (3×5 mL). The combinedorganics were dried over anhydrous Na₂SO₄, filtered, and concentratedunder reduced pressure. The crude material was purified by columnchromatography (SiO₂, 60% hexanes in ethyl acetate) to give the titlecompound (1.0 g, 2.3 mmol, 65% yield). MS (DCI/NH₃) m/z 440 (M+H)⁺.

Example 43C(Z)—N-(3-(3-aminopropyl)-5-methylthiazol-2(3H)-ylidene)-5-chloro-2-methoxybenzamide

To the product of Example 43B (0.95 g, 2.2 mmol) in CH₂Cl₂ at 0° C. wasadded trifluoroacetic acid (10 mL). This mixture was stirred at 0° C.for 5 min then was allowed to warm to ambient temperature and wasstirred for 1 h. The material was concentrated under reduced pressureand was purified via column chromatography (SiO₂, 9:1:0.1CH₂Cl₂:methanol:ammonium hydroxide) to give the title compound (0.40 g,1.2 mmol, 54% yield). MS (DCI/NH₃) m/z 340 (M+H)⁺.

Example 43D5-chloro-2-methoxy-N-[(2Z)-5-methyl-3-{3-[(methylsulfonyl)amino]propyl}-1,3-thiazol-2(3H)-ylidene]benzamide

To the product of Example 43C (0.22 g, 0.65 mmol) in tetrahydrofuran (7mL) was added triethyl amine (0.27 mL, 1.9 mmol) followed bymethanesulfonyl chloride (75 μL, 0.97 mmol). This mixture was stirred atambient temperature for 3 h then was quenched with saturated, aqueousNH₄Cl (5 mL) and was diluted with ethyl acetate (5 mL). The layers wereseparated and the aqueous layer was extracted with ethyl acetate (3×5mL). The combined organics were dried over anhydrous Na₂SO₄, filtered,concentrated under reduced pressure and purified via columnchromatography (SiO₂, 10% hexanes in ethyl acetate) to give the titlecompound (0.12 g, 0.29 mmol, 44% yield). ¹H NMR (300 MHz, CD₃OD) δ ppm2.02-2.13 (m, 2 H) 2.34 (d, J=1.4 Hz, 3 H) 2.81 (s, 3 H) 3.08 (t, J=6.6Hz, 2 H) 3.87 (s, 3 H) 4.34 (t, J=6.8 Hz, 2 H) 7.08 (d, J=9.2 Hz, 1 H)7.15 (q, J=1.2 Hz, 1 H) 7.40 (dd, J=9.0, 2.9 Hz, 1 H) 7.81 (d, J=2.7 Hz,1 H); MS (DCI/NH₃) m/z 418 (M+H)⁺; Anal. calculated for C₁₆H₂₀ClN₃O₄S₂:Calc: C, 45.98; H, 4.82; N, 10.05. Found: 46.00; H, 4.98; N, 9.98.

Example 445-chloro-2-methoxy-N-[(2Z)-5-methyl-3-[2-(4-methyl-1,3-thiazol-5-yl)ethyl]-1,3-thiazol-2(3H)-ylidene]benzamideExample 44A5-methyl-3-(2-(4-methylthiazol-5-yl)ethyl)thiazol-2(3H)-imine

To a solution of 4-methyl-5-thiazoleethanol (2 mL, 16.7 mmol) in CH₂Cl₂(10 mL) and pyridine (10 mL) was added p-toluenesulfonyl chloride (3.5g, 18.4 mmol) portionwise over 15 min. This mixture was stirred atambient temperature for 18 h then was quenched with 5% aqueous HCl (15mL). The layers were separated and the aqueous layer was extracted withCH₂Cl₂ (3×10 mL). The combined organics were dried over anhydrousNa₂SO₄, filtered, concentrated under reduced pressure and purified viacolumn chromatography (SiO₂, 50% hexanes/ethyl acetate) to give2-(4-methylthiazol-5-yl)ethyl 4-methylbenzenesulfonate (3.24 g, 10.9mmol, 65% yield). MS (DCI/NH₃) m/z 298 (M+H)⁺.

A mixture of 2-(4-methylthiazol-5-yl)ethyl 4-methylbenzenesulfonate(3.23 g, 10.9 mmol), 2-amino-5-methylthiazole (1.25 g, 10.9 mmol) andtetrabutyl ammonium iodide (2 g, 5.4 mmol) in N,N-dimethylformamide (2mL) was warmed to 85° C. and was stirred for 18 h. The mixture wascooled to ambient temperature, was diluted with CH₂Cl₂ (10 mL) and wasquenched with 10% NaOH (5 mL). The layers were separated and the aqueouslayer was extracted with CH₂Cl₂ (3×5 mL). The combined organics weredried over anhydrous Na₂SO₄, filtered, concentrated under reducedpressure and purified via column chromatography (SiO₂, 10% methanol inethyl acetate then 9:1:0.1 CH₂Cl₂:methanol:ammonium hydroxide) to givethe title compound (1.34 g, 5.6 mmol, 51% yield). MS (DCI/NH₃) m/z 240(M+H)⁺.

Example 44B5-chloro-2-methoxy-N-[(2Z)-5-methyl-3-[2-(4-methyl-1,3-thiazol-5-yl)ethyl]-1,3-thiazol-2(3H)-ylidene]benzamide

To a solution of the product of Example 44A (0.23 g, 0.97 mmol) intetrahydrofuran (5 mL) was added triethylamine (0.40 mL, 2.9 mmol)followed by Example 3D in tetrahydrofuran (5 mL) via cannula. Thismixture was warmed to 50° C. and was allowed to stir for 4 h. Themixture was cooled to ambient temperature and was quenched withsaturated, aqueous NH₄Cl (5 mL). The layers were separated and theaqueous layer was extracted with ethyl acetate (3×5 mL). The combinedorganics were dried over anhydrous Na₂SO₄, filtered, and concentratedunder reduced pressure. The crude material was purified by columnchromatography (SiO₂, 60% hexanes in ethyl acetate) to give the titlecompound (0.25 g, 0.61 mmol, 63% yield). ¹H NMR (300 MHz, CD₃OD) δ ppm2.27 (s, 3 H) 2.29 (d, J=1.4 Hz, 3 H) 3.40 (t, J=6.8 Hz, 2 H) 3.85 (s, 3H) 4.43 (t, J=6.8 Hz, 2 H) 6.94-6.99 (m, 1 H) 7.07 (d, J=9.2 Hz, 1 H)7.41 (dd, J=9.0, 2.9 Hz, 1 H) 7.84 (d, J=3.1 Hz, 1 H) 8.73 (s, 1 H); MS(DCI/NH₃) m/z 408 (M+H)⁺; Anal. calculated for C₁₈H₁₈ClN₃O₂S: Calc: C,53.00; H, 4.45; N, 10.30. Found: 52.92; H, 4.32; N, 10.15.

Example 452-[(tert-butylamino)oxy]-N-[(2Z)-5-tert-butyl-3-{[(2S)-5-oxopyrrolidin-2-yl]methyl}-1,3,4-thiadiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamideExample 45AN-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-2-fluoro-5-(trifluoromethyl)benzamide

To a solution of 5-tert-butyl-1,3,4-thiadiazol-2-amine (1.57 g, 10 mmol)and 2-fluoro-5-(trifluoromethyl)benzoyl chloride (2.27 g, 10 mmol) inCH₂Cl₂ (45 mL) at 0° C. was added dropwise triethylamine (1.7 mL, 12mmol) and the reaction mixture was allowed to warm to ambienttemperature for 12 h. The mixture was then washed with water, brine,dried with MgSO₄, and concentrated under reduced pressure to afford 3.2g of the title compound. MS (DCI/NH₃) m/z 348 (M+H)⁺.

Example 45B(S,Z)N-(5-tert-butyl-3-((5-oxopyrrolidin-2-yl)methyl)-1,3,4-thiadiazol-2(3H)-ylidene)-2-fluoro-5-(trifluoromethyl)benzamide

A mixture of Example 45A (348 mg, 1 mmol),(S)-(5-oxopyrrolidin-2-yl)methyl 4-methylbenzenesulfonate (Aldrich, 673mg, 2.5 mmol) and potassium carbonate (276 mg, 2 mmol) in toluene (25mL) was treated with tetrabutylammonium iodide (11 mg, 0.03 mmol),tetrabutylammonium hydrogen sulfate (10 mg, 0.03 mmol) andtetraethylammonium iodide (11 mg, 0.04 mmol) and the resulting mixturewas refluxed for 14 h The mixture was cooled to ambient temperature,washed with water, brine, dried with MgSO₄, and concentrated underreduced pressure. The residue was purified by chromatography(hexane-ethyl acetate 2:1) to afford 400 mg of the title compound. MS(DCI/NH₃) m/z 445 (M+H)⁺.

Example 45C2-[(tert-butylamino)oxy]-N-[(2Z)-5-tert-butyl-3-{[(2S)-5-oxopyrrolidin-2-yl]methyl}-1,3,4-thiadiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide

To a solution of N-tert-butylhydroxylamine [prepared from commerciallyavailable t-butylhydroxylamine acetate (Aldrich) by adding saturatedsodium bicarbonate solution and extracting the free base with ethylether) (461 mg, 5.2 mmol) and Example 45B (1.15 g, 2.6 mmol) inanhydrous tetrahydrofuran (50 mL) was added potassium tert-butoxide (1Nsolution in tetrahydrofuran) (5.2 mL, 5.2 mmol) and the reaction wasleft at 40° C. for 15 h. The solvent was removed under reduced pressureand the residue was partitioned between water and ethyl acetate. Theorganic layer was washed with brine, dried with MgSO₄ and concentratedunder reduced pressure. The residue was purified by chromatography(hexane-ethyl acetate 1:1) to provide 260 mg of the title compound. ¹HNMR (300 MHz, DMSO-d₆) δ ppm 1.07-1.15 (m, 9 H), 1.39 (s, 9 H),1.81-1.92 (m, 1 H), 2.05-2.24 (m, 3 H), 4.03-4.14 (m, 1 H), 4.22-4.36(m, 1 H), 4.39-4.58 (m, 1 H), 7.35 (s, 1 H), 7.70-7.88 (m, 3 H), 8.08(d, J=2.0 Hz, 1 H); MS (DCI/NH₃) m/z 514 (M+H)⁺. Anal. calculated forC₂₃H₃₀F₃N₅O₃S.0.5 ethyl acetate: C, 53.79; H, 5.89; N, 13.64. Found: C,53.49; H, 6.15; N, 12.56.

Example 46 tert-butyl2-[(2Z)-5-tert-butyl-2-[(5-chloro-2-methoxybenzoyl)imino]-1,3-thiazol-3(2H)-yl]ethylcarbamateExample 46A tert-butyl2-(5-tert-butyl-2-iminothiazol-3(2H)-yl)ethylcarbamate

A mixture of tert-butyl 2-aminoethylcarbamate (5.9 g, 37 mmol) and3,3-dimethylbutanal (4.9 mL 95%, 37 mmol) in 30 mL of dry acetonitrilewith 4 g of 4 Å (8-12 mesh beads) molecular sieves was stirred atambient temperature for 24 hours. The mixture was filtered throughCelite and washed with 5 mL of acetonitrile. Potassium thiocyanate (4.8g, 49 mmol) was added and the mixture warmed to 50° C. for 10 minutes.Iodine (9.3 g, 37 mmol) was added and the reaction stirred at 50° C. for6 hours. Acetonitrile (30 mL) was added followed by 10 mL of 20%Na₂S₂O₅. The layers were separated and the organic layer was dried withNa₂SO₄, filtered, and the solvent removed. The residue waschromatographed by equilibrating the column with CH₂Cl₂, loading thesample, and eluting with 5% methanol in CH₂Cl₂ (0.1% NH₄OH)isocratically to afford the title compound (3.5 g, 11.7 mmol, 32%yield). MS (DCI/NH₃) m/z 300.2 (M+H)⁺. ¹H NMR (300 MHz, CHLOROFORM-D) δppm 1.31 (s, 9 H) 1.42 (s, 9 H) 3.57 (q, J=6.78 Hz, 2 H) 4.26 (t, J=6.95Hz, 2 H) 5.63 (t, J=5.76 Hz, 1 H) 6.58 (s, 1 H).

Example 46B tert-butyl2-[(2Z)-5-tert-butyl-2-[(5-chloro-2-methoxybenzoyl)imino]-1,3-thiazol-3(2H)-yl]ethylcarbamate

Oxalyl chloride (6.5 mL, 2M in CH₂Cl₂) was added to5-chloro-2-methoxybenzoic acid (0.8 g, 4.3 mmol) in 8 mL of CH₂Cl₂followed by 20 μL of N,N-dimethylformamide. The reaction was stirred atambient temperature for 1 hour. The solvent was removed and the residuedried twice from toluene. The residue was suspended in 5 mL oftetrahydrofuran, Example 46A (1.3 g, 4.3 mmol) was added followed bytriethylamine (1.8 mL, 12.9 mmol) and the reaction was stirred atambient temperature for 1 hour. The reaction mixture was diluted with100 mL of ethyl acetate, the organic phase was washed with water, brine,dried with MgSO₄, filtered, and the solvent removed. The final productwas purified by flash chromatography using a gradient from hexane to 75%ethyl acetate in hexane over 750 mL then isocratic for 600 mL to affordthe title compound (1.7 g, 3.6 mmol, 85% yield). MS (DCI/NH₃) m/z 468.2(M+H)⁺. ¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.35 (s, 9 H) 1.39 (s, 9 H)3.57 (q, J=5.82 Hz, 2 H) 3.90 (s, 3 H) 4.33 (t, J=5.75 Hz, 2 H) 5.41 (s,1 H) 6.64 (s, 1 H) 6.91 (d, J=9.12 Hz, 1 H) 7.34 (dd, J=8.72, 2.78 Hz, 1H) 7.93 (d, J=2.78 Hz, 1 H).

Example 47N-[(2Z)-5-tert-butyl-3-[2-(methylamino)ethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 47A (Z)-tert-butyl2-(5-tert-butyl-2-(5-chloro-2-methoxybenzoylimino)thiazol-3(2H)-yl)ethyl(methyl)carbamate

Example 46B (0.5 g, 1.1 mmol) was dissolved in 4 mL ofN,N-dimethylformamide and cooled to 0° C., iodomethane (0.33 mL, 2.2mmol) was added followed by NaH (60% in mineral oil, 0.056 g, 1.4 mmol).The reaction mixture was allowed to warm to ambient temperature and stirfor 1 hour. Ethyl acetate (100 mL) was added and the organic phase waswashed with 20% NH₄Cl, water, brine, dried with MgSO₄, filtered, and thesolvent removed to provide the title compound (0.45 g, 0.9 mmol, 87%yield). LCMS m/z 482.2 (M+H)⁺.

Example 47BN-[(2Z)-5-tert-butyl-3-[2-(methylamino)ethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

Example 47A (0.45 g, 0.9 mmol) was dissolved in 10 mL of CH₂Cl₂, 2 mL oftrifluoroacetic acid was added the reaction mixture was stirred atambient temperature for 90 minutes. The solvent was removed and theresidue was twice dissolved in CH₂Cl₂ and solvent evaporated. Theresidue was dissolved in 5% methanol/CH₂Cl₂ (0.1% NH₄OH), filteredthrough silica and washed with 5% methanol/CH₂Cl₂ (0.1% ammoniumhydroxide) and the solvents evaporated to afford the title compound. MS(DCI/NH₃) m/z 382.2 (M+H)⁺. ¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.37(s, 9 H), 2.54 (s, 3 H), 3.47 (s, 2 H), 3.92 (s, 3 H), 4.54-4.62 (m, 2H), 6.82 (s, 1 H), 6.98 (d, J=8.82 Hz, 1 H), 7.43 (dd, J=8.81, 2.71 Hz,1 H), 7.80 (d, J=2.71 Hz, 1 H), 10.89 (s, 1 H).

Example 482-(azetidin-3-yloxy)-N-[(2Z)-5-tert-butyl-3-{[1-(methylsulfonyl)azetidin-3-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamideExample 48A (Z)-tert-butyl3-(2-(5-tert-butyl-3-((1-(methylsulfonyl)azetidin-3-yl)methyl)thiazol-2(3H)-ylidenecarbamoyl)-4-(trifluoromethyl)phenoxy)azetidine-1-carboxylate

Potassium t-butoxide (2.0 mL, IM in tetrahydrofuran) was added totert-butyl 3-hydroxyazetidine-1-carboxylate (0.37 g, 2.1 mmol) in 0.5 mLof tetrahydrofuran and stirred for 10 minutes. Example 42D (0.5 g, 1.0mmol) in 2.0 mL of tetrahydrofuran was added and the mixture stirred for1 hour. The mixture was diluted with ethyl acetate, washed withsaturated NaHCO₃, water, brine, dried with MgSO₄, filtered and thesolvent removed under reduced pressure. The residue was chromatographedto afford the title compound (0.58 g, 0.9 mmol, 89% yield). (solventA=hexane; solvent B=hexane:ethyl acetate:triethylamine (1:3:0.2); 100%solvent A to 100% B over 750 mL then isocratic for 180 mL). MS (DCI/NH₃)m/z 647.2 (M+H)⁺. ¹H NMR (300 MHz, DMSO-D6) δ ppm 1.33 (s, 9 H), 1.39(s, 9 H), 2.94 (s, 3 H), 3.76-3.85 (m, 4 H), 3.91 (t, J=8.3 Hz, 2 H),4.34 (dd, J=9.1, 6.7 Hz, 2 H), 4.40 (d, J=6.7 Hz, 2 H), 5.14 (ddd,J=10.2, 6.4, 4.0 Hz, 1 H), 7.01 (d, J=8.7 Hz, 1 H), 7.45 (s, 1 H), 7.74(dd, J=8.7, 2.4 Hz, 1 H), 8.01 (d, J=2.4 Hz, 1 H).

Example 48B2-(azetidin-3-yloxy)-N-[(2Z)-5-tert-butyl-3-{[1-(methylsulfonyl)azetidin-3-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide

Trifluoroacetic acid (1.4 mL 18 mmol) was added to Example 48A (0.58 g,0.9 mmol) in 6.0 mL of dichloromethane and stirred for 1 hour. Solventwas removed under reduced pressure and the residue dissolved in ethylacetate, washed with saturated NaHCO₃, water, brine, the organic layerdried with MgSO₄, filtered, and the solvent removed under reducedpressure. The residue was purified by flash chromatography to afford thetitle compound. (solvent A=hexane:ethyl acetate:triethylamine (1:3:0.2);solvent B=hexane:ethyl acetate:MeOH:triethylamine (1:3:2:0.2); 100%solvent A to 100% solvent B over 300 mL then isocratic for 600 mL).Pooled fractions were concentrated (0.14 g, 0.26 mmol, 29% yield), theresidue was dissolved in 3 mL of ethyl acetate, 65 mg of p-toluenesulfonic acid hydrate dissolved in 1 mL of ethyl acetate was added, then1 mL of hexane. The solution was cooled in the refrigerator overnight.The next day the solution was filtered, the precipitate was washed withhexane, diethyl ether, then dried under vacuum to provide the titlecompound as the bis-para-toluene sulfonate salt (75 mg). MS (ESI⁺) m/z547.1 (M+H)⁺. ¹H NMR (500 MHz, PYRIDINE-d₅) δ ppm 1.27 (s, 9 H), 3.11(s, 3 H), 3.23-3.35 (m, 1 H), 4.06-4.18 (m, 4 H), 4.66 (d, J=7.0 Hz, 2H), 4.73 (dd, J=11.9, 4.9 Hz, 2 H), 5.15 (dd, J=12.1, 6.6 Hz, 2 H),5.70-5.77 (m, 1 H), 7.07 (d, J=8.5 Hz, 1 H), 7.34 (s, 1 H), 7.64 (dd,J=8.5, 2.1 Hz, 1 H), 8.56 (d, J=2.1 Hz, 1 H). Analytical calculated forC₂₃H₂₉F₃N₄O₄S₂.2C₇H₈O₃S: C, 49.87; H, 5.09; N, 6.29. Found: C, 49.52; H,5.21; N, 6.31.

Example 495-chloro-N-[(2Z)-3-[(2-fluoropyridin-3-yl)methyl]-5-methyl-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamideExample 49A (2-fluoropyridin-3-yl)methyl methanesulfonate

To a solution of (2-fluoropyridin-3-yl)methanol (200 mg, 1.57 mmol) andtriethylamine (658 μL, 4.72 mmol) in CH₂Cl₂ (10 mL) was addedmethanesulfonyl chloride (269 mg, 2.36 mmol). The reaction mixture waskept at 0° C. for 30 min., poured into water, and the mixture wasextracted with CH₂Cl₂ (2×20 mL). The combined organic layers were driedover anhydrous Na₂SO₄, filtered, and concentrated under reducedpressure. The product was used without further purification.

Example 49B5-chloro-N-[(2Z)-3-[(2-fluoropyridin-3-yl)methyl]-5-methyl-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide

To a solution of Example 18A (100 mg, 0.31 mmol) inN,N-dimethylformamide:tetrahydrofuran (1:2, 20 mL) was added sodiumhydride (60% dispersion in mineral oil, 19 mg, 0.46 mmol). The mixturewas stirred at room temperature for 15 min. To this mixture was addedtetrabutylammonium iodide (5 mg) and Example 49A (201 mg, 1 mmol). Thereaction mixture was stirred at 75° C. for 12 hours, cooled, dilutedwith ethyl acetate (20 mL) and quenched with saturated aqueous NaHCO₃(20 mL). The aqueous layer was extracted with ethyl acetate (2×20 mL).The combined organic layers were washed with water (1×25 mL), dried overanhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by column chromatography using an Analogix®Intelliflash280 ™ (SiO₂, 10-100% ethyl acetate in hexanes) to afford14.5 mg (12%) of the title compound. ¹H NMR (500 MHz, CHLOROFORM-D) δppm 2.33 (s, 3 H) 3.91 (s, 3 H) 5.43 (s, 2 H) 6.89 (s, 1 H) 6.93 (d,J=8.85 Hz, 1 H) 7.24 (ddd, J=4.88, 1.53 Hz, 1 H) 7.38 (dd, J=8.85, 2.75Hz, 1 H) 7.92 (d, J=2.75 Hz, 1 H) 8.00 (t, J=9.46, 7.63 Hz, 1 H) 8.22(d, J=4.88 Hz, 1 H); MS (DCI/NH₃) m/z 392 (M+H)⁺.

Example 50N-[(2Z)-5-tert-butyl-3-{[(2R)-5-thioxopyrrolidin-2-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

A solution of Example 4D (263 mg, 0.62 mmol) in toluene was treated withLawesson's reagent (151 mg, 0.373 mmol) and the reaction mixture washeated at 80° C. for 6 hours. The reaction mixture was cooled to roomtemperature, and diluted with ethyl acetate, washed with a 10% solutionof sodium bicarbonate, brine, dried (anhydrous MgSO₄), filtered, andconcentrated under reduced pressure. Purification of the residue bycolumn chromatography (1:1 Hexane-ethyl acetate) provided the titlecompound (73 mg, 26% yield). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.23-1.42(m, 9 H), 1.87-2.04 (m, 1 H), 2.04-2.30 (m, 1 H), 2.56-2.81 (m, 1 H),3.78 (s, 3 H), 3.91-4.17 (m, 2 H), 4.34-4.65 (m, 2 H), 7.05-7.16 (m, 1H), 7.16-7.27 (m, 1 H), 7.44 (dd, J=9.0, 2.9 Hz, 1 H), 7.66 (d, J=2.7Hz, 1 H), 10.34 (s, 1 H). MS (DCI⁺) m/z 438 (M+H)⁺.

Example 51N-[(2Z)-5-tert-butyl-3-{[(2R)-5-thioxopyrrolidin-2-yl]methyl}-1,3,4-thiadiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

Example 7 and Lawesson's reagent were processed according to theprocedure described in Example 50 to provide the title compound (215 mg,63% yield). ¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.37-1.51 (m, 9 H),2.06-2.22 (m, 1 H), 2.37-2.60 (m, 1 H), 2.82-2.99 (m, 2 H), 3.94 (s, 3H), 4.29-4.51 (m, 1 H), 4.66-4.82 (m, 2 H), 6.87-7.00 (m, 1 H), 7.38(dd, J=9.0, 2.9 Hz, 1 H), 7.93 (d, J=3.1 Hz, 1 H), 8.53 (s, 1 H). MS(DCI+) m/z 439 (M+H)⁺.

Example 52N-[(2Z)-5-tert-butyl-3-{[(2S)-5-oxopyrrolidin-2-yl]methyl}-1,3,4-thiadiazol-2(3H)-ylidene]-2-methoxy-5-(trifluoromethyl)benzamide

The title compound was prepared according to the procedures described inExample 6, substituting Example 3D with commercially available5-trifluoromethyl-2-methoxybenzoyl chloride (228 mg, 59% yield). ¹H NMR(300 MHz, DMSO-d₆) δ ppm 1.35-1.46 (m, 9 H), 2.01-2.22 (m, 2 H), 2.74(t, J=6.9 Hz, 2 H), 3.87 (s, 3 H), 4.07-4.22 (m, 1 H), 4.23-4.38 (m, 1H), 4.40-4.56 (m, 1 H), 7.30 (d, J=8.7 Hz, 1 H), 7.71-7.93 (m, 2 H),8.57 (d, J=7.1 Hz, 1 H). MS (DCI+) m/z 457 (M+H)⁺ Anal. Calculated forC₂₀H₂₃F₃N₄O₃S: C, 52.62; H, 5.08; N, 12.27. Found: C, 52.71: H, 5.07; N,11.71.

Example 53N-[(2Z)-5-tert-butyl-3-{[(2R)-5-oxopyrrolidin-2-yl]methyl}-1,3,4-thiadiazol-2(3H)-ylidene]-2-methoxy-5-(trifluoromethyl)benzamide

The title compound was prepared according to the procedures described inExample 7, substituting Example 3D with commercially available5-trifluoromethyl-2-methoxybenzoyl chloride (230 mg, 60% yield). ¹H NMR(300 MHz, DMSO-d₆) δ ppm 1.36-1.46 (m, 9 H), 1.99-2.21 (m, 2 H), 2.74(t, J=7.0 Hz, 2 H), 3.87 (s, 3 H), 4.05-4.19 (m, 1 H), 4.24-4.38 (m, 1H), 4.40-4.61 (m, 1 H), 7.30 (d, J=8.5 Hz, 1 H), 7.71-7.86 (m, 2 H),8.57 (d, J=7.1 Hz, 1 H). MS (DCI+) m/z 457 (M+H)⁺. Anal. Calculated forC₂₀H₂₃F₃N₄O₃S: C, 52.62; H, 5.08; N, 12.27. Found: C, 52.73; H, 5.07; N,11.86.

Example 54N-[(2Z)-5-tert-butyl-3-[(1,3-dimethyl-1H-pyrazol-5-yl)methyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

The title compound was prepared according to the procedure described inExample 4D, substituting Example 4A with commercially available5-(chloromethyl)-1,3-dimethyl-1H-pyrazole (165 mg, 45% yield). ¹H NMR(300 MHz, DMSO-d₆) δ ppm 1.28-1.35 (m, 9 H), 2.08 (s, 3 H), 3.78 (d,J=3.4 Hz, 6 H), 5.36 (s, 2 H), 6.02 (s, 1 H), 7.11 (d, J=9.2 Hz, 1 H),7.35 (s, 1 H), 7.45 (dd, J=8.8, 3.1 Hz, 1 H), 7.64 (d, J=2.7 Hz, 1 H).MS (DCI+) m/z 434 (M+H)⁺. Anal. Calculated for C₂₁H₂₅ClN₄O₂S: C, 58.25;H, 5.82; N, 12.94. Found: C, 58.24; H, 5.69; N, 12.27.

Example 55N-[(2Z)-5-tert-butyl-3-{[(2S)-5-oxopyrrolidin-2-yl]methyl}-1,3,4-thiadiazol-2(3H)-ylidene]-2-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}-5-(trifluoromethyl)benzamide

The title compound was prepared according to the procedure described inExample 45C, substituting N-tert-butylhydroxylamine with commerciallyavailable (S)-5-(hydroxymethyl)pyrrolidin-2-one (130 mg, 56% yield). ¹HNMR (300 MHz, DMSO-d₆) δ ppm 1.39 (s, 9 H), 1.77-1.94 (m, 2 H),2.01-2.22 (m, 5 H), 2.22-2.39 (m, 1 H), 3.91 (dd, J=8.0, 3.9 Hz, 1 H),3.97-4.16 (m, 4 H), 4.17-4.34 (m, 1 H), 4.46 (dd, J=13.4, 7.6 Hz, 1 H),7.69 (s, 1 H), 7.80 (dd, J=9.0, 2.2 Hz, 1 H), 7.91-8.04 (m, 2 H) MS(DCI+) m/z 538 (M+H)⁺.

Anal. Calculated for C₂₄H₂₈F₃N₅O₄S: C, 52.37; H, 5.35; N, 12.72. Found:C, 52.29; H, 5.17; N, 12.41.

Example 56N-[(2Z)-5-tert-butyl-3-{[(2S)-5-oxopyrrolidin-2-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-5-(trifluoromethyl)benzamide

Example 57 and commercially available(S)-(1-methylpyrrolidin-2-yl)methanol were processed according to themethod described in Example 45C to provide the title compound (170 mg,47% yield). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.32 (s, 9 H), 1.49-1.74 (m,3 H), 1.73-1.95 (m, 2 H), 2.02-2.11 (m, 3 H), 2.16 (q, J=8.7 Hz, 1 H),2.31 (s, 3 H), 2.57 (dd, J=8.6, 5.9 Hz, 1 H), 2.81-3.01 (m, 1 H),3.97-4.16 (m, 4 H), 4.20-4.43 (m, 1 H), 7.18-7.38 (m, 2 H), 7.73 (dd,J=9.0, 2.2 Hz, 1 H), 7.83-8.00 (m, 2 H). MS (DCI+) m/z 538 (M+H)⁺. Anal.Calculated for C₂₆H₃₃F₃N₄O₃S C, 56.96; H, 6.14; N, 9.91. Found: C,56.96; H, 6.14; N, 9.91.

Example 57N-[(2Z)-5-tert-butyl-3-{[(2S)-5-oxopyrrolidin-2-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-2-fluoro-5-(trifluoromethyl)benzamide

The title compound was prepared according to the procedures described inExample 45A and Example 45B, substituting5-tert-butyl-1,3,4-thiadiazol-2-amine with Example 4B (300 mg, 62%yield). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.24-1.42 (m, 9 H), 1.75-1.92(m, 1 H), 2.00-2.20 (m, 3 H), 4.04-4.23 (m, 2 H), 4.23-4.46 (m, 1 H),7.35 (s, 1 H), 7.44-7.62 (m, 1 H), 7.81-8.00 (m, 2 H), 8.29 (dd, J=6.4,2.4 Hz, 1 H). MS (DCI+) m/z 444 (M+H)⁺.

Example 58N-[(2Z)-5-tert-butyl-3-{[(2S)-5-oxopyrrolidin-2-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-2-(pyridin-2-ylmethoxy)-5-(trifluoromethyl)benzamide

Example 57 and commercially available pyridin-2-ylmethanol wereprocessed according to the method described in Example 45C to providethe title compound (185 mg, 38% yield). ¹H NMR (300 MHz, DMSO-d₆) δ ppm1.24-1.42 (m, 9 H), 1.66-1.84 (m, 1 H), 1.88-2.13 (m, 3 H), 3.93-4.14(m, 2 H), 4.16-4.37 (m, 1 H), 5.36 (s, 2 H), 7.22-7.40 (m, 3 H), 7.61(d, J=7.9 Hz, 1 H), 7.68-7.92 (m, 3 H), 8.00 (d, J=2.4 Hz, 1 H), 8.57(d, J=4.0 Hz, 1 H). MS (DCI+) m/z 533 (M+H)⁺. Anal. Calculated forC₂₆H₂₇F₃N₄O₃S.0.5H₂O: C, 57.66; H, 5.21; N, 10.34. Found: C, 57.55; H,5.15; N, 10.43.

Example 59N-[(2Z)-3-[(2R)-2-aminopropyl]-5-tert-butyl-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 59A (R)-tert-butyl 2-methylaziridine-1-carboxylate

To a solution of (R)-tert-butyl 1-hydroxypropan-2-ylcarbamate (756 mg,4.31 mmol) and 4-methylbenzene-1-sulfonyl chloride (905 mg, 4.75 mmol)in ethyl ether (30 mL) was added powdered potassium hydroxide (968 mg,17.26 mmol) and reaction was refluxed for 2 hr. The reaction mixture waspoured into a separatory funnel that contained crushed ice and extractedwith ether (2×20 mL). The organics were combined, dried with sodiumsulfate, filtered, and concentrated. ¹H NMR (300 MHz, DMSO-d₆) δ ppm1.16 (d, J=5.43 Hz, 3 H) 1.38 (s, 9 H) 1.83 (d, J=3.73 Hz, 1 H) 2.17 (d,J=5.76 Hz, 1 H) 2.40 (qd, J=5.65, 3.73 Hz, 1 H).

Example 59B (R,Z)-tert-butyl1-(5-tert-butyl-2-(5-chloro-2-methoxybenzoylimino)thiazol-3(2H)-yl)propan-2-ylcarbamate

In a vial, a mixture of Example 4B (70 mg, 0.448 mmol) and Example 59A(225 mg, 1.43 mmol) was heated at 85° C. for 24 hr. The reaction mixturewas taken to the next step without further purification.

The above mixture was dissolved in CH₂Cl₂ (3 mL) andN,N-dimethylformamide (3 mL). N,N-dimethylpyridin-4-amine (109 mg, 0.896mmol) was added followed by addition of Example 3D (92 mg, 0.448 mmol)and the mixture was stirred for 24 hr. To the reaction was added waterand the mixture was extracted with CH₂Cl₂ (2×10 mL). The organics werecombined, washed with H₂O, dried (MgSO₄), filtered, and concentrated.The residue was triturated with CH₂Cl₂:hexane (1:2) and the resultingsolid was filtered (120 mg, 56%). ¹H NMR (300 MHz, CHLOROFORM-D) δ ppm1.23-1.27 (m, 3 H) 1.33-1.35 (m, 18 H) 3.90 (s, 3 H) 4.02-4.16 (m, 2 H)4.34-4.48 (m, 1 H) 5.73-5.75 (m, 1 H) 6.65-6.70 (m, 1 H) 6.89-6.93 (m, 1H) 7.33 (dt, J=8.73, 2.58 Hz, 1 H) 7.89-7.96 (m, 1 H); MS (DCI) m/z 482(M+H)⁺.

Example 59CN-[(2Z)-3-[(2R)-2-aminopropyl]-5-tert-butyl-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

In a 20 mL vial, to a solution of Example 59B (75 mg, 0.156 mmol) inMeOH (1 mL) was added a solution of hydrogen chloride (0.039 mL, 0.156mmol) in dioxane and the mixture was stirred for 24 hr. The reaction wasconcentrated and the residue was purified by preparative HPLC on aWaters Symmetry C8 column (25 mm×100 mm, 7 m particle size) using agradient of 10-100% acetonitrile (A) and 10 mM ammonium acetate in water(B), at a flow rate of 2.0 mL/min (0-0.1 min 10% A, 0.1-2.6 min 10-100%A, 2.6-2.9 min 100% A, 2.9-3.0 min 100-10% A. 0.5 min post-run delay) toobtain the title compound (32 mg, 59%). ¹H NMR (300 MHz, METHANOL-d₄) δppm 1.26 (d, J=6.78 Hz, 3 H) 1.40 (s, 9 H) 3.64-3.73 (m, 1 H) 3.86 (s, 3H) 4.26-4.31 (m, 2 H) 7.09 (d, J=8.82 Hz, 1 H) 7.18 (s, 1 H) 7.41 (dd,J=8.82, 2.71 Hz, 1 H) 7.74 (d, J=2.71 Hz, 1 H); MS (DCI) m/z 382 (M+H)⁺.

Example 602-[(2Z)-5-tert-butyl-2-[(5-chloro-2-methoxybenzoyl)imino]-1,3-thiazol-3(2H)-yl]ethylcarbamate Example 60A(Z)—N-(5-tert-butyl-3-(2-hydroxyethyl)thiazol-2(3H)-ylidene)-5-chloro-2-methoxybenzamide

To a solution of 3,3-dimethylbutanal (5 mL, 39.8 mmol) in acetonitrile(40 mL) were added molecular sieves (1 g) and 2-aminoethanol (2.433 g,39.8 mmol). The reaction mixture was stirred at room temperature for 48hr and then filtered. To the filtrate was added potassium thiocyanate(5.15 g, 53.0 mmol). The temperature was adjusted to 50° C. and themixture was stirred until the solids were dissolved. Then, iodine (10.11g, 39.8 mmol) was added to the mixture and stirred at 50° C. for 48 hr.The reaction mixture was cooled, concentrated and dissolved in ethylacetate (50 mL). The solution was washed with sodium meta-bisulfite(20%, 50 mL) by mixing the layers for 30 min. The aqueous layer wasisolated. The organic layer was washed twice with HCl (1 N, 50 mL). Theaqueous layers were combined and adjusted to pH=9 by adding NH₄OH. Theproduct was extracted with ethyl acetate (4×50 mL). The combined organicextracts were dried (Na₂SO₄), filtered, and concentrated to obtain thecrude mixture, which was used without further purification.

To a solution of the above mixture (2.21 g) in CH₂Cl₂ (20 mL) was addedtriethylamine (3.08 mL, 22.07 mmol), followed by addition of Example 3D(2.04 g, 9.93 mmol). The reaction was stirred overnight, washed withH₂O. The organic layer was separated, dried with Na₂SO₄, filtered,concentrated and the residue was purified using Analogix®Intelliflash280 ™ (SiO₂, 90-30% hexane in ethyl acetate over 25 min) in18% yield. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.32 (s, 9 H) 3.73-3.82 (m, 5H) 4.20 (t, J=5.35 Hz, 2 H) 4.92-4.99 (m, 1 H) 7.10 (d, J=9.12 Hz, 1 H)7.24 (s, 1 H) 7.44 (dd, J=8.72, 2.78 Hz, 1 H) 7.62 (d, J=2.78 Hz, 1 H);MS (DCI) m/z 369 (M+H)⁺.

Example 60B2-[(2Z)-5-tert-butyl-2-[(5-chloro-2-methoxybenzoyl)imino]-1,3-thiazol-3(2H)-yl]ethylcarbamate

To a solution of Example 60A (110 mg, 0.298 mmol) in CH₂Cl₂ (2 mL) wasadded trichloroacetyl isocyanate (67.4 mg, 0.358 mmol) and the mixturewas stirred for 2 hr. The reaction was concentrated and dissolved inmethanol (0.5 mL). A solution of potassium carbonate (140 mg, 1.013mmol) in water was added and the mixture was stirred for 24 hr. Thereaction was concentrated, partitioned between ethyl acetate (3×10 mL)and water (10 mL). The organics were combined, dried, filtered,concentrated and the residue was triturated with CH₂Cl₂ and hexane(1:3). The solid was collected by filtration (80 mg, 70%). ¹H NMR (300MHz, DMSO-d₆) δ ppm 1.32 (s, 9 H) 3.79 (s, 3 H) 4.29-4.38 (m, 4 H) 6.55(s, 1 H) 7.10 (d, J=9.12 Hz, 1 H) 7.19 (s, 1 H) 7.44 (dd, J=9.12, 2.78Hz, 1 H) 7.67 (d, J=2.78 Hz, 1 H); MS (DCI) m/z 412 (M+H)⁺. Anal calcdC₁₈H₂₂ClN₃O₄S.0.5H₂O: C, 51.36; H, 5.51; N, 9.98. Found: C, 51.23; H,5.33; N, 9.92.

Example 612-[(2Z)-2-{[2-azetidin-1-yl-5-(trifluoromethyl)benzoyl]imino}-5-tert-butyl-1,3-thiazol-3(2H)-yl]ethylazetidine-1-carboxylate Example 61A(Z)—N-(5-tert-butyl-3-(2-hydroxyethyl)thiazol-2(3H)-ylidene)-2-fluoro-5-(trifluoromethyl)benzamide

The title compound was prepared as described in Example 60A,substituting 2-fluoro-5-trifluorobenzoyl chloride for Example 3D. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 1.33 (s, 9 H) 3.80 (q, J=5.43 Hz, 2 H) 4.27 (t,J=5.59 Hz, 2 H) 4.94-4.98 (m, 1 H) 7.31 (s, 1 H) 7.48-7.55 (m, 1 H)7.89-7.96 (m, 1 H) 8.27 (dd, J=6.78, 2.71 Hz, 1 H); MS (DCI) m/z 391(M+H)⁺.

Example 61B(Z)-2-(5-tert-butyl-2-(2-fluoro-5-(trifluoromethyl)benzoylimino)thiazol-3(2H)-yl)ethylcarbonochloridate

To a solution of Example 61A (300 mg, 0.768 mmol) and triethylamine (233mg, 2.305 mmol) in Et₂O (5 mL) was added activated charcoal (10 mg,0.768 mmol), followed by addition of bis(trichloromethyl) carbonate (114mg, 0.384 mmol) and the mixture was stirred for 2 hr. The reaction wasfiltered, and concentrated to give the title compound as an oil (340 mg,0.751 mmol, 98%). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.33 (s, 9H) 3.80 (t,J=5.43 Hz, 2 H) 4.27 (t, J=5.43 Hz, 2 H) 7.32 (s, 1 H) 7.46-7.56 (m, 1H) 7.88-7.97 (m, 1 H) 8.24-8.33 (m, 1 H); MS (DCI) m/z 453 (M+H)⁺.

Example 61C2-[(2Z)-2-{[2-azetidin-1-yl-5-(trifluoromethyl)benzoyl]imino}-5-tert-butyl-1,3-thiazol-3(2H)-yl]ethylazetidine-1-carboxylate

To a solution of Example 61B (174 mg, 0.384 mmol) in CH₂Cl₂ (1.4 mL) wasadded azetidine (110 mg, 1.920 mmol) in methanol (0.5 mL) and themixture was stirred for 2 hr. The reaction mixture was concentrated andthe residue was purified by preparative HPLC on a Waters Symmetry C8column (25 mm×100 mm, 7 μm particle size) using a gradient of 10-100%acetonitrile (A) and 10 mM ammonium acetate in water (B), at a flow rateof 2.0 mL/min (0-0.1 min 10% A, 0.1-2.6 min 10-100% A, 2.6-2.9 min 100%A, 2.9-3.0 min 100-10% A. 0.5 min post-run delay) to obtain the titlecompound (38 mg, 0.074 mmol, 19.38%). ¹H NMR (300 MHz, DMSO-d₆) δ ppm1.32 (m, 9 H) 1.99-2.12 (m, 2 H) 2.18-2.29 (m, 2 H) 3.78 (t, J=7.29 Hz,4 H) 3.87 (t, J=7.46 Hz, 4 H) 4.35 (dd, J=14.24, 4.75 Hz, 4 H) 6.57 (d,J=8.82 Hz, 1 H) 7.27 (s, 1 H) 7.51 (dd, J=8.65, 1.86 Hz, 1 H) 7.87 (d,J=1.70 Hz, 1 H); MS (DCI) m/z 511 (M+H)⁺.

It is understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to be taken aslimitations upon the scope, which is defined solely by the appendedclaims and their equivalents. Various changes and modifications to thedisclosed embodiments will be apparent to those skilled in the art. Suchchanges and modifications, including without limitation those relatingto the chemical structures, substituents, derivatives, intermediates,syntheses, formulations and/or methods of use, may be made withoutdeparting from the spirit and scope thereof.

1. A compound of formula (I), or a pharmaceutically acceptable saltthereof,

wherein X is CR⁴; R¹ is phenyl or quinolin-8-yl wherein said phenyl issubstituted with one group represented by R¹⁰ and optionally furthersubstituted with 1, 2, or 3 groups represented by R^(11a); and whereinsaid quinolin-8-yl is optionally substituted with 1 or 2 groupsrepresented by R^(11b); R² is —NR^(23a)SO₂R^(105a), —NR^(23b)COR^(105b),—NR^(23b)CO(O)R^(105b), —NR^(23c)CONR^(101a)R^(102a),—NR^(23d)SO₂NR^(101b)R^(102b), —NR^(23e)R²⁴, —SO₂NR^(101c)R^(102c),—OC(O)NR^(101a)R^(102a), A¹, A², or A³; with the proviso that when X isCR⁴, R¹ is substituted phenyl, and R² is —OC(O)NR^(101a)R^(102a) whereinR^(101a) and R^(102a) are each independently hydrogen, alkyl,alkoxyalkyl, cycloalkyl, haloalkyl, or haloalkoxyalkyl, then R¹⁰ isother than haloalkoxyalkoxy, —O—NR^(23f)R^(23g),—O—(CR^(25b)R^(26b))_(u)-A⁴,—O—(CR^(25b)R^(26b))_(u)—C(═S)NR^(101d)R^(102d),—O—(CR^(25b)R^(26b))_(u)—C(O)NR^(101d)R^(102d),—O—(CR^(25b)R^(26b))_(u)—SO₂NR^(101d)R^(102d), and—O—(CR^(25b)R^(26b))_(q)—NR¹⁰³R¹⁰⁴; A¹ is a monocyclic heterocyclecontaining 1 or 2 nitrogen atoms and 0 or 1 sulfur atoms, wherein eachA¹ is independently unsubstituted or substituted with 1, 2, or 3substituents represented by R^(21a); A² is a bicyclic spiroheterocyclecontaining 1 or 2 nitrogen atoms and 0 or 1 sulfur atoms, wherein eachA² is independently unsubstituted or substituted with 1, 2, or 3substituents represented by R^(21b); A³ is imidazolyl, pyrazolyl,pyrrolyl, thiazolyl, thiadiazolyl, isothiazolyl, triazolyl, orpyridinyl, wherein each A³ is independently unsubstituted or substitutedwith 1, 2, or 3 substituents represented by R^(22a); R³ is hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl,hydroxyalkyl, haloalkyl, halo, cyano, or cyanoalkyl; with the provisothat when n is 1, R¹ is substituted phenyl, X is CR⁴ wherein R⁴ ishydrogen, R² is A³, and A³ is pyridinyl or 1,3-thiazolyl, then R³ isother than hydrogen; R⁴ is alkyl, alkenyl, alkynyl, cycloalkyl,hydrogen, or haloalkyl; R¹⁰ is alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl,alkenyl, alkynyl, alkylcarbonyl, cycloalkylalkyl, cyano, cyanoalkyl,formyl, halo, haloalkoxy, haloalkoxyalkoxy, haloalkyl,—CR^(106a)(═N—OR^(106b)), —O—NR^(23f)R^(23g),—O—(CR^(25b)R^(26b))_(u)-A⁴,—O—(CR^(25b)R^(26b))_(u)—C(═O)NR^(101d)R^(102d),—O—(CR^(25b)R^(26b))_(u)—C(═S)NR^(101d)R^(102d),—O—(CR^(25b)R^(26b))_(u)—SO₂NR^(101d)R^(102d),—O—(CR^(25b)R^(26b))_(q)—NR¹⁰³R¹⁰⁴, —NR^(23f)R^(23g),—NR^(23f)—(CR^(25b)R^(26b))_(u)-A⁴,—NR^(23f)—(CR^(25b)R^(26b))_(u)—C(═O)NR^(101d)R^(102d),—NR^(23f)—(CR^(25b)R^(26b))_(u)—C(═S)NR^(101d)R^(102d),—NR^(23f)—(CR^(25b)R^(26b))_(u)—SO₂NR^(101d)R^(102d),—NR^(23f)—(CR^(25b)R^(26b))_(q)—NR¹⁰³R¹⁰⁴, or A⁴; R^(11a) and R^(11b),at each occurrence, are each independently alkoxy, alkyl, alkenyl,alkynyl, alkylcarbonyl, cycloalkyl, cycloalkyloxy, cyano, cyanoalkyl,formyl, halo, haloalkoxy, haloalkoxyalkoxy, haloalkyl,—CR^(106a)(═N—OR^(106b)), furanyl, oxazolyl, oxadiazolyl, isoxazolyl,triazolyl, pyrazolyl, thiazolyl, oxetanyl, tetrahydrofuranyl, orpyranyl; R^(21a), R^(21b), R^(21c), and R^(21d), at each occurrence, areeach independently alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkoxy,alkoxyalkyl, halo, haloalkyl, haloalkoxy, haloalkoxyalkyl, oxo, ═S,hydroxy, cyano, cyanoalkyl, ═N—CN, ═N—OR^(106b),—CR^(106a)(═N—OR^(106b)), —CONR^(101d)R^(102d), —SO₂NR^(101d)R^(102d),—COR^(105d), —C(O)OR^(105c), or —SO₂R^(105c); R^(22a) and R^(22b), ateach occurrence, are each independently alkyl, alkenyl, alkynyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, halo, haloalkyl, haloalkoxy, haloalkoxyalkyl,hydroxy, cyano, cyanoalkyl, —CR^(106a)(═N—OR^(106b)),—CONR^(101d)R^(102d), —SO₂NR^(101d)R^(102d), —COR^(105d),—C(O)OR^(105c), or —SO₂R^(105c); R^(23a), R^(23b), R^(23c), R^(23d),R^(23e), R^(23f), and R^(23g) are each independently hydrogen, alkyl,cycloalkyl, haloalkyl, alkoxyalkyl, or haloalkoxyalkyl; R²⁴ is alkyl,haloalkyl, alkoxyalkyl, haloalkoxyalkyl, or A⁵; A⁴ and A⁵, at eachoccurrence, are each independently a cycloalkyl, a monocyclicheterocycle that is optionally substituted with 1, 2, or 3 substituentsrepresented by R^(21c); a bicyclic spiroheterocycle that is optionallysubstituted with 1, 2, or 3 substituents represented by R^(21d); or amonocyclic heteroaryl that is optionally substituted with 1, 2, or 3substituents represented by R^(22b); R^(25a) and R^(26a), at eachoccurrence, are each independently hydrogen, alkyl, cyclopropyl,cyclobutyl, cyclopentyl, halo, haloalkyl, or alkoxy; R^(25a) and R^(26a)taken together with the carbon atom to which they are attachedoptionally form a monocyclic ring selected from the group consisting ofcyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; wherein each ofthe cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl isindependently unsubstituted or substituted with 1, 2, 3, 4, 5, or 6substituents independently selected from the group consisting of alkyl,halo, haloalkyl, alkoxy, oxo, hydroxy, cyano, and haloalkoxy; R^(25b)and R^(26b), at each occurrence, are each independently hydrogen, alkyl,cyclopropyl, cyclobutyl, cyclopentyl, halo, haloalkyl, or alkoxy;R^(101a), R^(101b), R^(101c), R^(102a), R^(102b), and R^(102c), at eachoccurrence, are each independently hydrogen, alkyl, alkoxyalkyl,cycloalkyl, haloalkyl or haloalkoxyalkyl; R^(101a) and R^(102a), orR^(101b) and R^(102b), or R^(101c) and R^(102c), together with therespective nitrogen atom to which they are attached optionally form a4-7 membered monocyclic heterocycle; wherein said monocyclic heterocyclecontains 0 or 1 additional heteroatom, 0 or 1 double bond, and isoptionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of alkyl, alkoxy, haloalkyl, halo,hydroxy, and oxo; R^(101d) and R^(102d), at each occurrence, are eachindependently hydrogen, alkyl, alkoxyalkyl, cycloalkyl, haloalkyl orhaloalkoxyalkyl; R^(101d) and R^(102d), together with the nitrogen atomto which they are attached, optionally form a 4-7 membered monocyclicheterocycle; wherein said monocyclic heterocycle contains 0 or 1additional heteroatom, 0 or 1 double bond, and is optionally substitutedwith 1, 2, or 3 substituents independently selected from the groupconsisting of alkyl, alkoxy, haloalkyl, halo, hydroxy, and oxo; R¹⁰³ ishydrogen, alkyl, haloalkyl, or alkoxyalkyl; R¹⁰⁴ is hydrogen, alkyl,alkylcarbonyl, alkylsulfonyl, alkoxyalkyl, cycloalkyl, haloalkyl, orhaloalkoxyalkyl; R^(105a), R^(105b), and R^(105c), at each occurrence,are each independently alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl,haloalkyl, or cyanoalkyl; R^(105d), at each occurrence, is independentlyhydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, haloalkyl, orcyanoalkyl; R^(106a) and R^(106b), at each occurrence, are eachindependently hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl,sec-butyl, isobutyl, tert-butyl, cyclopropyl, or cyclobutyl; n is 1, 2,3, or 4; u is 0, 1, 2, 3, or 4; q is 2, 3, or 4, and each occurrence ofthe cycloalkyl, the cycloalkyl moiety of the cycloalkylalkyl and thecycloalkyloxy, the cyclopropyl, the cyclobutyl, and the cyclopentyl, asrepresented by R³, R⁴, R¹⁰, R^(11a), R^(11b), R^(23a), R^(23b), R^(23c),R^(23d), R^(23e), R^(23f), R^(23g), A⁴, A⁵, R^(25a), R^(26a), R^(25b),R^(26b), R^(101a), R^(101b), R^(101c), R^(101d), R^(102a), R^(102b),R^(102c), R^(102d), R¹⁰⁴, R^(105a), R^(105b), R^(105c), R^(105d),R^(106a), and R^(106b), are each independently unsubstituted orsubstituted with 1, 2, 3, 4, 5, or 6 substituents independently selectedfrom the group consisting of alkyl, halo, haloalkyl, alkoxy, oxo,hydroxy, cyano, and haloalkoxy.
 2. The compound of claim 1 havingformula (I), or a pharmaceutically acceptable salt thereof, wherein R²is —NR^(23a)SO₂R^(105a), —NR^(23b)C(O)OR^(105B), —NR^(23e)R²⁴,—SO₂NR^(101c)R^(102c), or —OC(O)NR^(101a)R^(102a).
 3. The compound ofclaim 1 having formula (I), or a pharmaceutically acceptable saltthereof, wherein R² is A¹, A², or A³.
 4. The compound of claim 1 havingformula (I-A), or a pharmaceutically acceptable salt thereof

wherein y is 0, 1, 2, or
 3. 5. The compound of claim 4 having formula(I-A), or a pharmaceutically acceptable salt thereof wherein R² is—NR^(23a)SO₂R^(105a), —NR^(23b)C(O)OR^(105B), —NR^(23e)R²⁴,—SO₂NR^(101c)R^(102c), or —OC(O)NR^(101a)R^(102a).
 6. The compound ofclaim 4 having formula (I-A), or a pharmaceutically acceptable saltthereof wherein R² is —NR^(23a)SO₂R^(105a), —NR^(23b)C(O)OR^(105B),—NR^(23e)R²⁴, —SO₂NR^(101c)R^(102c), or —OC(O)NR^(101a)R^(102a); and R³is C₁₋₆ alkyl, optionally substituted cycloalkyl, halo, haloalkyl, orhydroxyalkyl.
 7. The compound of claim 4 having formula (I-A), or apharmaceutically acceptable salt thereof wherein R² is A¹, A², or A³. 8.The compound of claim 4 having formula (I-A), or a pharmaceuticallyacceptable salt thereof wherein R² is A¹, R³ is C₁₋₆ alkyl, optionallysubstituted cycloalkyl, halo, haloalkyl, or hydroxyalkyl.
 9. Thecompound of claim 4 having formula (I-A), or a pharmaceuticallyacceptable salt thereof wherein R² is A³, R³ is C₁₋₆ alkyl, optionallysubstituted cycloalkyl, halo, haloalkyl, or hydroxyalkyl.
 10. Thecompound of claim 1 having formula (I-D), or a pharmaceuticallyacceptable salt thereof

wherein z is 0, 1, or
 2. 11. The compound according to claim 1 or apharmaceutically acceptable salt thereof, selected from the groupconsisting ofN-[(2Z)-5-tert-butyl-3-{[1-(methylsulfonyl)azetidin-3-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-2-methoxy-5-(trifluoromethyl)benzamide;N-[(2Z)-5-tert-butyl-3-{[1-(cyclopropylsulfonyl)azetidin-3-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-2-methoxy-5-(trifluoromethyl)benzamide;5-chloro-2-methoxy-N-[(2Z)-5-methyl-3-{[1-(methylsulfonyl)azetidin-3-yl]methyl}-1,3-thiazol-2(3H)-ylidene]benzamide;N-[(2Z)-5-tert-butyl-3-{[(2R)-5-oxopyrrolidin-2-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-{[(2S)-5-oxopyrrolidin-2-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-{[1-(methylsulfonyl)azetidin-3-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-{2-[methyl(methylsulfonyl)amino]ethyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-[2-(dimethylamino)ethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-{2-[(methylsulfonyl)amino]ethyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-{2-[(ethylsulfonyl)(methyl)amino]ethyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;5-chloro-N-[(2Z)-3-[(6-fluoropyridin-3-yl)methyl]-5-methyl-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide;N-[(2Z)-3-[(2R)-azetidin-2-ylmethyl]-5-tert-butyl-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;5-chloro-N-[(2Z)-5-chloro-3-(1,3-thiazol-4-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide;N-[(2Z)-5-bromo-3-(1,3-thiazol-4-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;5-chloro-2-methoxy-N-[(2Z)-5-methyl-3-(1,3-thiazol-4-ylmethyl)-1,3-thiazol-2(3H)-ylidene]benzamide;2,5-dichloro-N-[(2Z)-5-methyl-3-[(2-methyl-1,3-thiazol-4-yl)methyl]-1,3-thiazol-2(3H)-ylidene]benzamide;5-chloro-2-methoxy-N-[(2Z)-5-methyl-3-[(2-methyl-1,3-thiazol-4-yl)methyl]-1,3-thiazol-2(3H)-ylidene]benzamide;5-chloro-2-methoxy-N-[(2Z)-5-methyl-3-(1,3-thiazol-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]benzamide;5-chloro-2-methoxy-N-[(2Z)-5-methyl-3-[(4-methyl-1,3-thiazol-2-yl)methyl]-1,3-thiazol-2(3H)-ylidene]benzamide;5-chloro-N-[(2Z)-3-[(6-chloropyridin-3-yl)methyl]-5-methyl-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide;5-chloro-2-methoxy-N-[(2Z)-5-methyl-3-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-1,3-thiazol-2(3H)-ylidene]benzamide;N-[(2Z)-5-tert-butyl-3-(1,3-thiazol-4-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;2-ethoxy-N-[(2Z)-5-methyl-3-[3-(1H-pyrrol-1-yl)propyl]-1,3-thiazol-2(3H)-ylidene]benzamide;5-chloro-2-methoxy-N-[(2Z)-5-methyl-3-[3-(1H-pyrrol-1-yl)propyl]-1,3-thiazol-2(3H)-ylidene]benzamide;N-[(2Z)-5-tert-butyl-3-[(2S)-pyrrolidin-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-[(2S)-piperidin-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-[(2R)-piperidin-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-{[(2S)-1-methylpyrrolidin-2-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-{[(2S)-1-methylpiperidin-2-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-{[(2R)-1-methylpiperidin-2-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-{[(2R)-1-ethylpiperidin-2-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-[(3R)-piperidin-3-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-[(2R)-pyrrolidin-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-[2-(2-oxopyrrolidin-1-yl)ethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-[2-(2-oxopiperidin-1-yl)ethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-[2-(2-oxoimidazolidin-1-yl)ethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;(Z)—N-(5-tert-butyl-3-(2-sulfamoylethyl)thiazol-2(3H)-ylidene)-2-methoxy-5-(trifluoromethyl)benzamide;N-[(2Z)-5-tert-butyl-3-{[1-(methylsulfonyl)azetidin-3-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-5-(trifluoromethyl)benzamide;5-chloro-2-methoxy-N-[(2Z)-5-methyl-3-{3-[(methylsulfonyl)amino]propyl}-1,3-thiazol-2(3H)-ylidene]benzamide;5-chloro-2-methoxy-N-[(2Z)-5-methyl-3-[2-(4-methyl-1,3-thiazol-5-yl)ethyl]-1,3-thiazol-2(3H)-ylidene]benzamide;tert-butyl2-[(2Z)-5-tert-butyl-2-[(5-chloro-2-methoxybenzoyl)imino]-1,3-thiazol-3(2H)-yl]ethylcarbamate;N-[(2Z)-5-tert-butyl-3-[2-(methylamino)ethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;2-(azetidin-3-yloxy)-N-[(2Z)-5-tert-butyl-3-{[1-(methylsulfonyl)azetidin-3-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;5-chloro-N-[(2Z)-3-[(2-fluoropyridin-3-yl)methyl]-5-methyl-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-{[(2R)-5-thioxopyrrolidin-2-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-[(1,3-dimethyl-1H-pyrazol-5-yl)methyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-{[(2S)-5-oxopyrrolidin-2-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-5-(trifluoromethyl)benzamide;N-[(2Z)-5-tert-butyl-3-{[(2S)-5-oxopyrrolidin-2-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-2-fluoro-5-(trifluoromethyl)benzamide;N-[(2Z)-5-tert-butyl-3-{[(2S)-5-oxopyrrolidin-2-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-2-(pyridin-2-ylmethoxy)-5-(trifluoromethyl)benzamide;2-[(2Z)-5-tert-butyl-2-[(5-chloro-2-methoxybenzoyl)imino]-1,3-thiazol-3(2H)-yl]ethylcarbamate; and2-[(2Z)-2-{[2-azetidin-1-yl-5-(trifluoromethyl)benzoyl]imino}-5-tert-butyl-1,3-thiazol-3(2H)-yl]ethylazetidine-1-carboxylate.
 12. A pharmaceutical composition comprising atherapeutically effective amount of a compound of formula (I) accordingto claim 1, or a pharmaceutically acceptable salt thereof, incombination with one or more pharmaceutically acceptable carrier.
 13. Amethod for treating pain in a mammal in need of such treatmentcomprising administering to the mammal a therapeutically effectiveamount of a compound of formula (I) according to claim 1, or apharmaceutically acceptable salt thereof.